Compounds with hydroxycarbonyl-halogenoalkyl side chains

ABSTRACT

The present invention provides a compound consisting of a moiety and a group chemically bonded to said moiety, wherein said moiety contains a compound having low activity following oral administration or its parent scaffold and said group has the following general formula (1): 
                         
in which
         R 1  represents a hydrogen atom, etc.,   R 2  represents a C 1 –C 7  halogenoalkyl group, etc.,   m represents an integer of 2 to 14, and   n represents an integer of 2 to 7,
 
or enantiomers of the compound, or hydrates or pharmaceutically acceptable salts of the compound or enantiomers thereof. The above compound is advantageous in pharmaceutical use because the group of general formula (1) allows compounds such as anti-estrogenic ones to show a significantly increased activity following oral administration when attached to the parent scaffolds of the compounds.

This is a division of parent application Ser. No. 10/149,752, filed Jun.13, 2002, now U.S. Pat. No. 6,737,417 which is the national stage under35 U.S.C. §371 of international application PCT/JP00/08810.

TECHNICAL FIELD

The present invention relates to hydroxycarbonyl-halogenoalkylderivatives designed to significantly increase oral activity ofcompounds having low activity following oral administration, compoundshaving anti-tumor activity, compounds having estrogenic activity orcompounds having anti-estrogenic activity.

BACKGROUND ART

In treating diseases caused by abnormal tissue growth that is dependentupon a certain sexual steroidal hormone such as estrogen, it is highlyimportant to significantly inhibit, more preferably completelyeliminate, the effect induced by the hormone. For this purpose, it isdesirable to reduce the level of hormone capable of acting on thesteroidal hormone receptor site. For instance, anti-estrogenic agentsare commonly administered for alternative or combination therapy tolimit the production of estrogen to the amount less than required toactivate the receptor site. However, such conventional technique forblocking estrogen production could not sufficiently inhibit the effectinduced through the estrogen receptor. Practically, even when estrogenis completely absent, some of the receptors may be activated. It wastherefore considered that estrogen antagonists could provide bettertherapeutic effect in comparison to the technique for blocking only theproduction of sexual steroidal hormone. Thus, numerous estrogenantagonists have been developed. For example, many patent publicationsincluding U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661, 5,395,842 andWO 96/22092 disclose various anti-estrogenic compounds. Sometimes,however, prior art antagonists may themselves act as agonists, andtherefore activate rather than block the receptor. For example,Tamoxifen has been most widely used as an anti-estrogenic agent.However, this agent has a disadvantage that it exhibits estrogenicactivity in some organs (see, M. Harper and A. Walpole, J. Reprod.Fertile., 1967, 13, 101).

As another non-steroidal anti-estrogenic compound, WO 93/10741 disclosesa benzopyran derivative having an aminoethoxyphenyl substituent(s)(Endorecherche), the typical compound of which is EM-343 having thefollowing structure:

Said compound also has the agonistic effect. It is therefore required todevelop an anti-estrogenic compound which is substantially or completelyfree of agonistic effect and which can effectively block the estrogenreceptor.

In addition, it has been known that 7α-substituted derivatives ofestradiol, for example, 7α-(CH₂)₁₀CONMeBu derivatives, are steroidalanti-estrogenic agents without agonistic effect (see, EP-A 0138504, U.S.Pat. No. 4,659,516). Further, an estradiol derivative having a7α-(CH₂)₉SOC₅H₆F₅ substituent has also been disclosed as a7α-substituted derivative of estradiol (see, Wakeling et al., CancerRes., 1991, 51, 3867).

Non-steroidal anti-estrogenic agents without agonistic effect have beenfirst reported by Wakeling et al. in 1987 (see, A. Wakeling and Bowler,J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661discloses phenol derivatives having anti-estrogenic activity. Thesephenol derivatives generally have a naphthalene scaffold and include,typically, the following compounds:

Some chroman and thiochroman derivatives have been reported asanti-estrogenic compounds having no agonistic effect (WO 98/25916).Although the existing anti-estrogenic compounds having no agonisticeffect show a substantial therapeutic effect when administered viaintravenous or subcutaneous injection, they show a highly reducedtherapeutic effect when administered orally, due to their lowbioavailability by oral route. Therefore, for convenience's sake in thecase of administration, it is desired to develop anti-estrogeniccompounds which show a sufficient effect when administered orally and atthe same time have no agonistic effect. Also, it is generally desired todevelop agents which show a sufficient effect when administered orally.

DISCLOSURE OF THE INVENTION

The object of the present invention is to providehydroxycarbonyl-halogenoalkyl derivatives designed to significantlyincrease oral activity of compounds having low activity following oraladministration, compounds having anti-tumor activity, compounds havingestrogenic activity or compounds having anti-estrogenic activity byenhancing their absorption from the intestinal tract and/or improvingtheir stability against metabolism.

Our research efforts were directed to achieving the above object, and wehave found that a side chain of general formula (1) allowed estrogeniccompounds to show a significantly increased activity by oral route whenattached to the parent scaffolds of the compounds. The present inventionhas been accomplished on the basis of this finding.

Namely, the present invention provides a compound consisting of a moietyand a group chemically bonded to said moiety, wherein said moietycontains a compound having low activity following oral administration orits parent scaffold and said group has the following general formula(1):

in which

R₁ represents a hydrogen atom or a salt-forming metal,

R₂ represents a linear or branched C₁–C₇ halogenoalkyl group,

m represents an integer of 2 to 14, and

n represents an integer of 2 to 7,

or enantiomers of the first-mentioned compound, or hydrates orpharmaceutically acceptable salts of the compound or enantiomersthereof.

The present invention also provides a compound consisting of a moietyand a group chemically bonded to said moiety, wherein said moietycontains a compound having anti-tumor activity or its parent scaffoldand said group has the following general formula (1):

in which

R₁ represents a hydrogen atom or a salt-forming metal,

R₂ represents a linear or branched C₁–C₇ halogenoalkyl group,

m represents an integer of 2 to 14, and

n represents an integer of 2 to 7,

or enantiomers of the first-mentioned compound, or hydrates orpharmaceutically acceptable salts of the first-mentioned compound orenantiomers thereof.

The present invention further provides a compound consisting of a moietyand a group chemically bonded to a moiety, wherein said moiety containsa compound having estrogenic activity or its parent scaffold or acompound having anti-estrogenic activity or its parent scaffold and saidgroup has the following general formula (1):

in which

R₁ represents a hydrogen atom or a salt-forming metal,

R₂ represents a linear or branched C₁–C₇ halogenoalkyl group,

m represents an integer of 2 to 14, and

n represents an integer of 2 to 7,

or enantiomers of the first-mentioned compound, or hydrates orpharmaceutically acceptable salts of the first-mentioned compound orenantiomers.

The present invention even further provides a compound having thefollowing general formula (2):

in which

R₁ represents a hydrogen atom or a salt-forming metal,

R₂ represents a linear or branched C₁–C₇ halogenoalkyl group,

m represents an integer of 2 to 14,

n represents an integer of 2 to 7, and

A represents a group selected from the following formulae (3) to (8) and(10) to (26):

in which

-   -   in formulae (6), (7), (14) and (24), each of R₃ and R₆        represents a linear or branched C₁–C₅ alkyl group,    -   in formulae (10), (11) and (12), Z₁₀ represents a hydrogen atom        or an acyl group,    -   in formulae (13), (21) and (22), each of Z₁, Z₂, Z₃, Z₄, Z₅ and        Z₆ independently represents a hydrogen atom, a hydroxyl group or        a linear or branched C₁–C₅ alkyl group,    -   in formula (15), R₇ represents a hydrogen atom or a linear or        branched C₁–C₅ alkyl group,    -   in formula (16), each of Z₇, Z₈ and Z₉ independently represents        a hydrogen atom or a hydroxyl group,    -   in formulae (18) and (20), R₈ represents a linear or branched        C₁–C₅ alkyl group, a linear or branched C₂–C₅ alkenyl group or a        linear or branched C₂–C₅ alkynyl group,    -   in formula (23), each of R₂₁, R₂₂, R₂₃ and R₂₄ independently        represents a hydrogen atom, a linear or branched C₁–C₅ alkyl        group, a linear or branched C₁–C₇ halogenoalkyl group, a halogen        atom or an acyl group, and    -   in formulae (25) and (26), X represents a halogen atom,        or enantiomers of the compound, or hydrates or pharmaceutically        acceptable salts of the compound or enantiomers thereof.

Furthermore, the present invention provides a pharmaceutical compositioncomprising a compound of general formula (2) as an active ingredient.The present invention also provides an anti-estrogenic pharmaceuticalcomposition comprising the above compound as an active ingredient. Thepresent invention further provides a therapeutic agent for breast cancercomprising a compound of general formula (2) as an active ingredient.

As used herein, the term “parent scaffold(s)” refers to a partialstructure shared by a class of compounds having the same or similarpharmacological effects or physicochemical properties. The parentscaffolds include, but are not limited to, the following structures:steroid, indole, naphthalene, benzofuran, benzothiophene, benzopyran,benzoxazine, 3,4-diphenyl-[4.3.0]-nonane,4-(1,2-diphenyl-1-butenyl)phenol, flavone, erythromycin, alkaloid,cephalosporin, β-lactam, and derivatives thereof.

Compounds having low activity following oral administration refer tothose compound which are incapable of showing adequate activity for adesired pharmacological effect when administered orally because they arepoorly absorbed from the intestinal tract or rapidly metabolized in thebody. Examples include certain types of anti-tumor compounds, certaintypes of estrogenic compounds (e.g., estradiol) and anti-estrogeniccompounds.

Compounds having anti-tumor activity include all types of compoundscapable of inhibiting tumor growth. The present invention isparticularly advantageous to those compounds showing low activity byoral route.

Compounds having estrogenic activity refer to those compounds which haveaffinity for the estrogen receptor and enhance the signaling mediated bythe estrogen receptor. Examples include estradiol.

Compounds having anti-estrogenic activity refer to those compounds whichhave an antagonistic activity against estrogen's pharmacologicaleffects. Examples include the compounds described in the prior artreports mentioned above.

The present invention provides compounds wherein a moiety is chemicallybonded to a group, wherein said moiety containing a compound having lowactivity following oral administration, a compound having anti-tumoractivity, a compound having estrogenic activity or a compound havinganti-estrogenic activity or the parent scaffolds of these compounds andsaid group having the general formula (1). As used herein, the term“chemically bonded” means that the group is bonded through a covalentbond and the like, including a C—C bond, a C—O bond, a C—N bond, etc.The moiety containing the above-mentioned compounds or their parentscaffolds may take any structure as long as these bonds are possible. AC—C bond is preferably used to improve stability against metabolism andhence activity by oral route.

Salt-forming metals as R₁ include, but are not limited to, alkali metalssuch as sodium and potassium, alkaline earth metals such as magnesiumand calcium, rare earth metals such as cerium and samarium, as well aszinc and tin. Among these, alkali metals and alkaline earth metals arepreferred.

R₁ may preferably be a hydrogen atom, an alkali metal and an alkalineearth metal.

Halogens in the linear or branched C₁–C₇ halogenoalkyl groups as R₂include fluorine, chlorine, bromine and iodine, with fluorine beingpreferred. R₂ may contain one or more halogen atoms. When R₂ containstwo or more halogen atoms, they may be the same or different, preferablythe same halogen atoms. In particular, R₂ is preferably aperhalogenoalkyl group. Alkyls in the linear or branched C₁–C₇halogenoalkyl groups under consideration include, but are not limitedto, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, n-hexyl and n-heptyl. Preferred are linear or branchedC₁–C₄ alkyls, i.e., methyl, ethyl, n-propyl, i-propyl and n-butyl.

Examples of the linear or branched C₁–C₇ perhalogenoalkyl group as R₂include the above-listed linear or branched C₁–C₇ alkyl groups, providedthat they are perhalogenated, preferably perfluorinated. Also preferredare perhalogenated linear or branched C₁–C₅ alkyl groups and a group ofthe following general formula (9):

in which each of R₄ and R₅ which may be the same or different representsa linear or branched C₁–C₃ perhalogenoalkyl group. Among them,perfluorinated groups are preferred. More specifically, aperfluoromethyl group, a perfluoroethyl group, a perfluoro-n-propylgroup and a perfluoro-n-butyl group are particularly preferred.

In the case where R₂ in general formula (2) is a group of generalformula (9), examples of the linear or branched C₁–C₃ perhalogenoalkylgroup as R₄ and R₅ include the above-listed linear or branched C₁–C₃alkyl groups, provided that they are perhalogenated, preferablyperfluorinated. Further, perhalogenated C₁ alkyl groups are preferredand a perfluorinated group is particularly preferred. More specifically,a perfluoromethyl group is preferred.

In the case where R₂ in general formula (2) is a group of generalformula (9), R₂ is preferably a 1,1,1,3,3,3-hexafluoroisopropyl group.

Having the definition given above, R₂ is preferably a perfluoroethylgroup, a perfluoro-n-propyl group, a perfluoro-n-butyl group, and a1,1,1,3,3,3-hexafluoro-isopropyl group.

Examples of the linear or branched C₁–C₅ alkyl group as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl and 1-ethylpropyl.

Examples of the linear or branched C₂–C₅ alkenyl group as used hereininclude, but are not limited to, vinyl, allyl, 1-butenyl, 2-butenyl and3-butenyl.

Examples of the linear or branched C₂–C₅ alkynyl group as used hereininclude, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyland 3-butynyl.

Examples of the acyl group as used herein include, but are not limitedto, alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, caproyl and phenylacetyl;alkenylcarbonyl groups such as acryloyl, propyoloyl, methacryloyl,crotonoyl and isocrotonoyl; and arylcarbonyl groups such as benzoyl.

Examples of the linear or branched C₁–C₇ halogenoalkyl group as R₂₁,R₂₂, R₂₃ and R₂₄ may be the same groups as previously listed for R₂.

Group A may preferably be any one of the groups having formulae (3) to(8) and (10) to (23), particularly groups having formulae (3) to (6),(17) to (20) and (23), and more particularly groups having formulae (3),(4) and (17) to (20).

m may preferably be an integer of 4 to 10.

n may preferably be an integer of 2 to 7.

The group of general formula (1), which is one component of the compoundaccording to the present invention, has an asymmetric center, while theother component may have an asymmetric center. Further, the compound ofgeneral formula (2) according to the present invention may have anasymmetric center in group A in addition to the asymmetric center in thegroup of general formula (1). For this reason, the compounds of thepresent invention have enantiomers. All individual enantiomers andmixtures thereof are intended to be within the scope of the presentinvention. When group A having an asymmetric center is a steroidscaffold represented by any one of formulae (3), (4) and (17) to (20),the group of general formula (1) is preferably attached to the steroidparent scaffold at 7α- or 11β-position.

Also, in the general formulae(1) and (2), both compounds with R- andS-configulation of the asymmetric carbon to which carboxylic acid or itsmetal salt is attached are preferable.

Among compounds of general formula (2), preferred are those compounds inwhich R₁ is a hydrogen atom, an alkali metal or an alkaline earth metal;R₂ is a perfluoroethyl group, a perfluoro-n-propyl group, aperfluoro-n-butyl group or a 1,1,1,3,3,3-hexafluoroisopropyl group; m isan integer of 4 to 10; and n is an integer of 2 to 6.

The compounds of the present invention may be obtained as hydrates.

Pharmaceutically acceptable salts include, but are not limited to, theabove-mentioned metal salts, for example, sodium, potassium and calciumsalts.

The compound according to the present invention may be administered as apharmaceutical composition in any dosage form suitable for the intendedroute of administration, in combination with one or morepharmaceutically acceptable diluents, wetting agents, emulsifiers,dispersants, auxiliary agents, preservatives, buffers, binders,stabilizers and the like. The compound and composition may beadministered parenterally or orally.

The dose of the compound can be suitably determined according to thephysique, age and physical condition of a patient, severity of thedisease to be treated, elapsed time after onset of the disease, etc.Because the compound of the present invention is expected to show asignificantly high activity by oral route, it is generally used in anamount of 0.1 to 500 mg/day when orally administered and in an amount of0.1–1000 mg/day to 0.1–1000 mg/month when parenterally administered (byintravenous, intramuscular, or subcutaneous route) for adult patient.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound of general formula (1), particularly the compound ofgeneral formula (2), can be prepared according to any one of thefollowing Reaction Schemes A to K and 1 to 19. In these Reaction SchemesA to K and 1 to 19 (i.e., Processes A to K and 1 to 19), R₂, R₃, R₆, R₇,Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Z₇, Z₈, Z₉, Z₁₀, m and n are as defined above ingeneral formulae (1) and (2); each of R₁₁, R₁₂, R₁₃ and R₁₆ represents aprotecting group; R₃₃ represents a linear or branched alkyl group; eachof Y₁, Y₂, Y₃, Y₄, Y₅ and Y₆ independently represents a hydrogen atom,an alkyl group (e.g., a linear or branched C₁–C₅ alkyl group) or OR₁₁;each of L₁ and L₂ represents a leaving group; X represents a halogenatom; m₁ is m-2; R₈ represents a linear or branched C₁–C₅ alkyl group, alinear or branched C₂–C₅ alkenyl group or a linear or branched C₂–C₅alkynyl group.

The compound of the present invention may include various stereoisomersbecause it contains one or more asymmetric carbon atoms. To obtain asingle stereoisomer, there are two techniques, one of which uses achiral column to resolve a mixture of stereoisomers and the otherinvolves asymmetric synthesis. The chiral column technique may becarried out using a column commercially available, from DAICEL under thetrade name of CHIRALPAK-OT(+), OP(+) or AD, or CHIRALCEL-OA, OB, OJ, OK,OC, OD, OF or OG, for example. Regarding asymmetric synthesis, Processes14 to 16 illustrate the asymmetric synthesis of the inventive compoundwith respect to an asymmetric carbon atom, to which a side chaincarboxyl group is attached.

Note: Compound (I) can be synthesized by the method described in J. Org.Chem., 60(1995) 5316–5318.

in which

R₈ represents a linear or branched C₁–C₅ alkyl group, a linear orbranched C₂–C₅ alkenyl group or a linear or branched C₂–C₅ alkynylgroup, and

M represents a metal.

in which

R₈ represents a linear or branched C₁–C₅ alkyl group, a linear orbranched C₂–C₅ alkenyl group or a linear or branched C₂–C₅ alkynylgroup, and

M represents a metal.

in which

each of Y₁, Y₂ and Y₃ independently represents a hydrogen atom, an alkylgroup (e.g., a linear or branched C₁–C₅ alkyl group) or OR₁₁, and

each of Z₁, Z₂ and Z₃ independently represents a hydrogen atom, ahydroxyl group or a linear or branched C₁–C₅ alkyl group.

in which

each of Y₁, Y₂, Y₃, Y₄, Y₅ and Y₆ independently represents a hydrogenatom, an alkyl group (e.g., a linear or branched C₁–C₅ alkyl group) orOR₁₁, and

each of Z₁, Z₂, Z₃, Z₄, Z₅ and Z₆ independently represents a hydrogenatom, a hydroxyl group or a linear or branched C₁–C₅ alkyl group.

In the above Reaction Schemes 14 and 15(Processes 14 and 15), R₂, R₁₁,R₁₂, X, m, n, X, L₁ and L₂ are as defined above, R* represents a chiralauxiliary, and m and m₃ are integers that satisfy the relation m=m₃+3.

[Process A]

Process A illustrates the synthesis of compound (VI) starting withcompound (I). Compound (I) can be synthesized by the method described inJ. Org. Chem., 60(1995) 5316–5318.

Step 1: Preparation of Compound (III)

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (I)is reacted with compound (II) in a solvent (e.g., methylene chloride,chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethylsulfoxide or dimethylformamide) at a temperature ranging from −78° C. tothe boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (III).

Step 2: Preparation of Compound (IV)

Using a catalyst (e.g., palladium on activated carbon, palladiumhydroxide, platinum oxide or Wilkinson's catalyst), compound (III) ishydrogenated in an inert solvent (e.g., methanol, ethanol, ethylacetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane,chloroform or benzene) at a temperature ranging from room temperature tothe boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (IV).

Step 3: Preparation of Compound (V)

When R₁₁ is, for example, a methyl group, compound (IV) is treated withan acid (e.g., hydrogen chloride, sulfuric acid, hydrogen bromide,pyridine hydrochloride or boron tribromide) at a temperature rangingfrom −78° C. to the boiling point of the reaction mixture to givecompound (V).

Step 4: Preparation of Compound (VI)

Compound (V) is treated with sodium hydroxide or potassium hydroxide ina solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or awater/methanol mixture) at a temperature ranging from room temperatureto the boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (VI).

[Process B]

As shown below, compound (VI) given by Process A can also be preparedstarting with compound (I) in the following manner.

Step 1: Preparation of Compound (VIII)

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (I)is reacted with compound (VII) in a solvent (e.g., methylene chloride,chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethylsulfoxide or dimethylformamide) at a temperature ranging from −78° C. tothe boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (VIII).

Step 2: Preparation of Compound (IX)

Using a catalyst (e.g., palladium on activated carbon, palladiumhydroxide, platinum oxide or Wilkinson's catalyst), compound (VIII) ishydrogenated in an inert solvent (e.g., methanol, ethanol, ethylacetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane,chloroform or benzene) at a temperature ranging from room temperature tothe boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (IX).

Step 3: Preparation of Compound (X)

Compound (IX) is treated with sodium hydroxide or potassium hydroxide ina solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or awater/methanol mixture) at a temperature ranging from room temperatureto the boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (X).

Step 4: Preparation of Compound (XI)

In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene,toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in thepresence of an acid (e.g., hydrogen chloride, sulfuric acid orp-toluenesulfonic acid), compound (X) is heated to a temperature rangingfrom 50° C. to the boiling point of the reaction mixture to givecompound (XI).

Step 5: Preparation of Compound (VI)

When R₁₁ is, for example, a methyl group, compound (XI) is treated withan acid (e.g., hydrogen chloride, sulfuric acid, hydrogen bromide,pyridine hydrochloride or boron tribromide) at a temperature rangingfrom −78° C. to the boiling point of the reaction mixture to givecompound (VI).

[Process C]

As shown below, compound (VI) given by Processes A and B can also beprepared starting with compound (XII) in the following manner.

Step 1: Preparation of Compound (XIV)

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XII)is reacted with compound (XIII) in a solvent (e.g., methylene chloride,chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethylsulfoxide or dimethylformamide) at a temperature ranging from −78° C. tothe boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (XIV).

Step 2: Preparation of Compound (IV)

Compound (XIV) is dehydrated using an acid (e.g., hydrochloric acid,hydrobromic acid, hydrobromic acid/acetic acid) in an inert solvent(e.g., methanol, ethanol) at a temperature ranging from room temperatureto the boiling point of the reaction mixture, preferably at 50° C., andfurther processed by hydrogenation analogous to Process A to givecompound (IV).

Step 3: Preparation of Compound (VI)

Compound (IV) is subjected to hydrolysis and deprotection analogous toProcess A or B to give compound (VI).

[Process D]

As shown below, compound (VI) given by Processes A, B and C can also beprepared starting with compound (XII) in the following manner.

Step 1: Preparation of Compound (XVI)

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XII)is reacted with compound (XV) in a solvent (e.g., methylene chloride,chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethylsulfoxide or dimethylformamide) at a temperature ranging from −78° C. tothe boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (XVI).

Step 2: Preparation of Compound (XVII)

Compound (XVI) is dehydrated using an acid (e.g., hydrochloric acid,hydrobromic acid, hydrobromic acid/acetic acid) in an inert solvent(e.g., methanol, ethanol) at a temperature ranging from room temperatureto the boiling point of the reaction mixture, preferably at 50° C., andfurther processed by hydrogenation analogous to Process A to givecompound (XVII).

Step 3: Preparation of Compound (VI)

Compound (XVII) is subjected to hydrolysis, decarboxylation anddeprotection by a procedure analogous to Process A or B to give compound(VI).

Compound (XII) used as a starting material in Processes C and D can beprepared according to the method described in Tetrahedron., 30(1977) pp.609–616.

[Process E]

Process E illustrates the synthesis of compound (XXIX) starting withcompound (XXI).

Step 1: Preparation of Compound (XXII)

In the presence of an organic base (e.g., triethylamine or pyridine),compound (XXI) is treated with an acid chloride (e.g., methanesulfonylchloride or p-toluenesulfonyl chloride) in an inert solvent (e.g.,tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform,preferably dichloromethane) at a temperature ranging from roomtemperature to the boiling point of the reaction mixture, preferably atroom temperature, to convert (CH₂)_(m)OH in compound (XXI) into(CH₂)_(m)-L₁, in which L₁ is —O—SO₂CH₃ or —O—SO₂—C₆H₄-p-CH₃, forexample. The compound thus obtained is then treated with a metal halide(e.g., sodium iodide or potassium iodide) in an inert solvent (e.g.,acetone, tetrahydrofuran, dioxane, dichloromethane, dichloroethane orchloroform, preferably acetone) at a temperature ranging from roomtemperature to the boiling point of the reaction mixture, preferably atthe boiling point of the reaction mixture, to give compound (XXII).

Step 2: Preparation of Compound (XXIV)

In the presence of a base (e.g., sodium hydride, sodium hydroxide orpotassium t-butoxide), compound (XXII) is reacted with a malonic ester(XXIII) (e.g., diethyl malonate or dimethyl malonate) in an inertsolvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethaneor chloroform, preferably tetrahydrofuran) at a temperature ranging fromroom temperature to the boiling point of the reaction mixture to givecompound (XXIV).

Step 3: Preparation of Compound (XXVI)

In the presence of a base (e.g., sodium hydride, sodium hydroxide orpotassium t-butoxide), compound (XXIV) is reacted with an alkyl halide(XXV), in which L₂ represents a halogen atom, in an inert solvent (e.g.,tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform,preferably tetrahydrofuran) at a temperature ranging from roomtemperature to the boiling point of the reaction mixture to givecompound (XXVI).

Step 4: Preparation of Compound (XXVII)

Compound (XXVI) is treated with sodium hydroxide or potassium hydroxidein a solvent (e.g., water, ethanol, methanol, a water/ethanol mixture ora water/methanol mixture) at a temperature ranging from room temperatureto the boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound (XXVII).

Step 5: Preparation of Compound (XXVIII)

In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene,toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in thepresence of an acid (e.g., hydrogen chloride, sulfuric acid orp-toluenesulfonic acid), compound (XXVII) is heated to a temperatureranging from 50° C. to the boiling point of the reaction mixture to givecompound (XXVIII).

Step 6: Preparation of Compound (XXIX)

When R₁₁ is, for example, a methyl group, compound (XXVIII) is treatedwith an acid (e.g., hydrogen chloride, sulfuric acid, hydrogen bromide,pyridine hydrochloride or boron tribromide) at a temperature rangingfrom −78° C. to the boiling point of the reaction mixture to givecompound (XXIX).

Compound (XXI) used as a starting material in Process E can be preparedaccording to the method described in DE4218743A1.

[Process F]

Compound (XXIX) given by Process E can also be prepared starting withcompound (XXII) according to the following steps.

Step 1: Preparation of Compound (XXXI)

In the presence of a base (e.g., sodium hydride, sodium hydroxide orpotassium t-butoxide), compound (XXII) is reacted with compound (XXX) inan inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane,dichloroethane or chloroform, preferably tetrahydrofuran) at atemperature ranging from −78° C. to the boiling point of the reactionmixture to give compound (XXXI).

Step 2: Preparation of Compound (XXIX)

Compound (XXXI) is converted into compound (XXIX) by a procedureanalogous to Process E.

[Process G]

Process G illustrates the synthesis of compound (ILVIII) starting withcompound (ILI).

Step 1: Preparation of Compound (ILIII)

In the presence of a base (e.g., sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, barium hydroxide, lithiumhydroxide, sodium hydride, preferably potassium carbonate), compound(ILI) is reacted with compound (ILII) in an inert solvent (e.g.,acetone, methyl ethyl ketone, tetrahydrofuran, preferably acetone) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably at room temperature, to give compound (ILIII).

Step 2: Preparation of Compound (ILIV) Via Claisen Rearrangement

Compound (ILIII) is dissolved in an inert solvent (e.g., N,N-dimethylaniline, N,N-diethyl aniline, nitrobenzene, dichlorobenzene,dibromobenzene, preferably N,N-dimethyl aniline) and then heated to atemperature ranging from 180° C. to the boiling point of the reactionmixture, preferably from 180° C. to 200° C., to give compound (ILIV).

Step 3: Preparation of Compound (ILV)

In the presence of a base (e.g., triethylamine, diethylisopropylamine,pyridine, sodium carbonate, potassium carbonate, sodium hydroxide,potassium hydroxide, sodium hydride, preferably pyridine), compound(ILIV) is reacted with Tf₂O (trifluoromethanesulfonic anhydride) in aninert solvent (e.g., dichloromethane, chloroform, benzene, toluene,preferably dichloromethane) at a temperature ranging from 0° C. to roomtemperature to give compound (ILV).

Step 4: Preparation of Compound (ILVII)

In the presence of a palladium or nickel catalyst, compound (ILV) isreacted with compound (ILVI) in an inert solvent (e.g., ether,tetrahydrofuran, dioxane, dimethylformamide, water, preferably dioxane)at a temperature ranging from room temperature to the boiling point ofthe reaction mixture, preferably at the boiling point of the reactionmixture, to give compound (ILVII).

Step 5: Preparation of Compound (ILVIII)

Compound (ILVII) is converted into compound (ILVIII) by a procedureanalogous to Process A, B, C or D.

[Process H]

Process H illustrates the synthesis of compound (LIV) starting withcompound (LI) synthesized by the method described in U.S. Pat. No.4,904,661.

Step 1: Preparation of Compound (LII)

Compound (LI) is reacted with a reducing agent (e.g., lithium aluminumhydride, diisobutylaluminum hydride, sodium borohydride) in an inertsolvent (e.g., tetrahydrofuran, dioxane, diethyl ether) at a temperatureranging from 0° C. to the boiling point of the reaction mixture,preferably from 0° C. to 50° C., to give compound (LII).

Step 2: Preparation of Compound (LIII)

In the presence of a suitable acid (e.g., zinc iodide, borontrifluoride), compound (LII) is reacted with allyl-trimethylsilane in aninert solvent (e.g., dichloroethane, dichloromethane, chloroform) at atemperature ranging from 0° C. to the boiling point of the reactionmixture, preferably from 0° C. to 50° C., to give compound (LIII).

Step 3: Preparation of Compound (LIV)

Compound (LIII) is subjected to analogous procedure to Process A, B, Cor D, that is, metathesis, reduction, hydrolysis, decarboxylation,deprotection, etc. to give compound (LIV).

[Process I]

Compound (LIV) can also be synthesized starting with compound (LI) inthe following manner.

Step 1: Preparation of Compound (LVI)

In the presence of a base (e.g., sodium hydride, n-butyllithium,t-butyllithium, lithium diisopropylamide, potassium tert-butoxide),compound (LI) is reacted with compound (LV) in an inert solvent (e.g.,tetrahydrofuran, dioxane, diethyl ether) at a temperature ranging from−78° C. to the boiling point of the reaction mixture, preferably from−78° C. to 0° C., to give compound (LVI).

Step 2: Preparation of Compound (LVII)

In the presence of a suitable acid (e.g., zinc iodide, borontrifluoride), compound (LVI) is reacted with sodium cyanoborohydride inan inert solvent (e.g., dichloroethane, dichloromethane, chloroform) ata temperature ranging from 0° C. to the boiling point of the reactionmixture, preferably from 0° C. to 50° C., to give compound (LVII).

Step 3: Preparation of Compound (LVIII)

In the presence of a catalyst (e.g., palladium on activated carbon,palladium hydroxide, platinum oxide), compound (LVII) is hydrogenated inan inert solvent (e.g., methanol, ethanol, ethyl acetate,tetrahydrofuran, dioxane, preferably tetrahydrofuran, ethyl acetate) ata temperature ranging from room temperature to the boiling point of thereaction mixture, preferably at room temperature, to give compound(LVIII). Compound (LVIII) can be directly prepared form compound (LVI)through hydrogenation using a catalyst (e.g., palladium on activatedcarbon, palladium hydroxide or platinum oxide) in an inert solvent(e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane,preferably tetrahydrofuran, ethyl acetate) at a temperature ranging fromroom temperature to the boiling point of the reaction mixture,preferably at room temperature.

Step 4: Preparation of Compound (LIV)

Compound (LVIII) is reacted by a procedure analogous to Process E or Fto give compound (LIV).

[Process J]

Process J illustrates the synthesis of compound (LXII) starting withcompound (LIX).

Step 1: Preparation of Compound (LXI)

In the presence of a base (e.g., sodium hydride, n-butyllithium,potassium tert-butoxide), compound (LIX) is reacted with compound (LX)in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane,diethyl ether, dimethyl sulfoxide) at a temperature ranging from 0° C.to the boiling point of the reaction mixture, preferably from 0° C. to50° C., to give compound (LXI).

Step 2: Preparation of Compound (LXII)

Compound (LXI) is subjected to metathesis, reduction, hydrolysis anddeprotection by a procedure analogous to Process A, B, C or D to givecompound (LXII).

[Process K]

Compound (LXII) can also be synthesized starting with compound (LIX) inthe following manner.

Step 1: Preparation of Compound (LXIV)

In the presence of a base (e.g., sodium hydride, n-butyllithium,potassium tert-butoxide), compound (LIX) is reacted with compound(LXIII) in an inert solvent (e.g., dimethylformamide, tetrahydrofuran,dioxane, diethyl ether, dimethyl sulfoxide) at a temperature rangingfrom 0° C. to the boiling point of the reaction mixture, preferably from0° C. to 50° C., to give compound (LXIV).

Step 2: Preparation of Compound (LXII)

Compound (LXIV) is reacted by a procedure analogous to Process E or F togive compound (LXII).

Compounds of general formula (2) in which group A is represented byformula (8) can be prepared, for example, as shown in Examples 6 to 10by the same or equivalent procedure.

[Process 1]

Compound 2 is prepared starting with compound 1 by a procedure analogousto Process E. Compound 1 used as a starting material can be preparedaccording to the method described in WO99/64393.

[Process 2]

Compound 4 is prepared starting with compound 3 by a procedure analogousto Process E. Compound 5 can be obtained by oxidizing compound 4according to the method described in WO99/64393. Compound 3 used as astarting material can be prepared according to the method described inWO99/64393.

[Process 3]

Process 3 illustrates the synthesis of compound 9 starting with compound6. Compound 6 used as a starting material can be synthesized by, forexample, the methods described in J. Org. Chem., 50(1985) 2121–2123 andJ. Org. Chem., 61(1996) 3890–3893.

Step 1: Preparation of Compound 8

In the presence of a base (e.g., sodium hydride, n-butyllithium,potassium tert-butoxide), compound 6 is reacted with compound 7 in aninert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane,diethyl ether, dimethyl sulfoxide) at a temperature ranging from 0° C.to the boiling point of the reaction mixture, preferably from 0° C. to50° C., to give compound 8.

Step 2: Preparation of Compound 9 Compound 8 is reacted by a procedureanalogous to Process E to give compound 9.

[Process 4]

Process 4 illustrates the synthesis of compound 20 starting withcompound 10.

Step 1: Preparation of Compound 11

In the presence of an acid catalyst such as sulfuric acid, compound 10is heated in an alcohol (e.g., methanol, ethanol) at a temperatureranging from −78° C. to the boiling point of the reaction mixture,preferably at the boiling point of the reaction mixture, to givecompound 11.

Step 2: Preparation of Compound 12

Amino and hydroxyl groups of compound 11 prepared in Step 1 areprotected to give compound 12.

Step 3: Preparation of Compound 13

Compound 12 is treated with a reducing agent (e.g., lithium borohydride,etc.) in a solvent (e.g., methanol, ethanol or ethanol/tetrahydrofuran)at a temperature ranging from −78° C. to the boiling point of thereaction mixture, preferably at room temperature, to give compound 13.

Step 4: Preparation of Compound 15

Compound 13 is subjected to Mitsunobu reaction with compound 14 to givecompound 15.

Step 5: Preparation of Compound 16

Compound 15 is subjected to deprotection of the amino group to givecompound 16.

Step 6: Preparation of Compound 17

In the presence of a base (e.g., potassium carbonate, potassiumt-butoxide, sodium t-butoxide), compound 16 is reacted by addition of ametal catalyst such as palladium along with a ligand such asdiphenylphosphino ferrocene or2,2-bis(diphenylphosphino)-1,1′-binaphthyl, preferably by addition of atris(dibenzylideneacetone)dipalladium catalyst along with2,2-bis(diphenylphosphino)-1,1′-binaphthyl, in an inert solvent (e.g.,benzene, toluene, xylene, dioxane or tetrahydrofuran) at a temperatureranging from −78° C. to the boiling point of the reaction mixture,preferably at 100° C., to give compound 17.

Step 7: Preparation of Compound 19

In the presence of a base (e.g., sodium hydride, n-butyllithium,potassium tert-butoxide, potassium carbonate) and, if necessary, byaddition of a reagent such as sodium iodide, compound 17 is reacted withcompound 18 in an inert solvent (e.g., dimethylformamide,tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide, acetone) ata temperature ranging from 0° C. to the boiling point of the reactionmixture, preferably at the boiling point of the reaction mixture, togive compound 19.

Step 8: Preparation of Compound 20

Compound 19 is reacted by a procedure analogous to Process A or B togive compound 20.

[Process 5]

Process 5 illustrates the synthesis of compound 27 starting withcompound 21.

Step 1: Preparation of Compound 23

Compound 21 is subjected to protection with TBS, then reacted withaldehyde 22, and then protected at its amino group, to give compound 23.

Step 2: Preparation of Compound 25

Compound 23 prepared in Step 1 is alkylated with compound 24 to givecompound 25.

Step 3: Preparation of Compound 26

Compound 25 is subjected to deprotection of the amino group and thentreated with a reducing agent (e.g., lithium aluminum hydride, etc.) ina solvent (e.g., tetrahydrofuran, ether) at a temperature ranging from−78° C. to the boiling point of the reaction mixture, preferably at roomtemperature, to give compound 26.

Step 4: Preparation of Compound 27

Compound 26 is reacted by a procedure analogous to Process 4 to givecompound 27.

[Process 6]

Process 6 illustrates the synthesis of compound 35 starting withcompound 28.

Compound 35 can be synthesized starting with compound 28 in thefollowing manner.

Step 1: Preparation of Compound 29

Compound 29 is prepared from compound 28 by the method described inSynthesis, 12(1995) 1493–1495 or by an equivalent method.

Step 2: Preparation of Compound 32

In the presence of a base (e.g., lithium hexamethyl-disilazide, sodiumhexamethyl-disilazide, potassium hexamethyl-disilazide, sodium hydride,n-butyllithium, t-butyllithium, lithium diisopropylamide, potassiumtert-butoxide, aqueous potassium hydroxide, aqueous sodium hydroxide),compound 29 is reacted with compound 30 or 31 in an inert solvent (e.g.,1,2-dimethoxyethane, tetrahydrofuran, dioxane, t-butyl methyl ether,diethyl ether, dimethyl sulfoxide, N,N-dimethylformamide,N,N-dimethylacetamide, toluene) at a temperature ranging from −78° C. tothe boiling point of the reaction mixture, preferably from −78° C. to 0°C., to give compound 32.

Step 3: Preparation of Compound 33

Compound 32 is isomerized under a basic condition (e.g.,tetrabutylammonium fluoride/tetrahydrofuran, sodium methoxide/methanol,sodium ethoxide/ethanol, potassium methoxide/methanol, sodiummethoxide/propanol, aqueous potassium hydroxide, aqueous sodiumhydroxide), followed by deprotection of R₁₂ and purification viarecrystallization, to give a single isomer of formula 33. In the casewhere R₁₂ is a t-butyldimethylsilyl group, compound 32 is isomerizedsimultaneously with the removal of TBS by treatment withtetrabutylammonium fluoride and further purified via recrystallizationto give the single isomer of formula 33.

Step 4: Preparation of Compound 34

In the presence of a suitable acid (e.g., trifluoroacetic acid, borontrifluoride etherate, titanium tetrachloride, aluminum chloride,trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid),compound 33 is reacted with triethylsilane in an inert solvent (e.g.,dichloroethane, dichloromethane, chloroform, t-butyl methyl ether,toluene) at a temperature ranging from 0° C. to the boiling point of thereaction mixture, preferably from 0° C. to room temperature, to givecompound 34.

Step 5: Preparation of Compound 35

Compound 34 is reacted by a procedure analogous to Process A or B togive compound 35.

[Process 7]

Process 7 illustrates the synthesis of compound 38 starting withcompound 36.

Compound 38 can be synthesized starting with compound 37 by a procedureanalogous to Process 3. Compounds 36 and 37 used as starting materialscan be synthesized by the methods described in J. Med. Chem., 40(1997)2117–2122 and J. Med. Chem., 33(1990) 3222–3229 or by equivalentmethods.

[Process 8]

Process 8 illustrates the synthesis of compound 40 starting withcompound 39.

Compound 40 can be synthesized starting with compound 39 by a procedureanalogous to Process 3. Compound 39 used as a starting material can besynthesized by, for example, the methods described in EP0826670A1 and J.Org. Chem., 60(1995) 739–741.

[Process 9]

Compound 42 or 43 can be synthesized in the following manner. Compound42 can be synthesized from compound 41 by Jones oxidation, PCCoxidation, Swern oxidation, or ruthenium oxidation (e.g., TPAP) of the17-hydroxyl group. Compound 42 is further reacted with R₈-M, in which R₈represents a lower alkyl group or a lower alkenyl group or a loweralkynyl group and M represents a metal such as lithium, sodium,potassium, magnesium, calcium or aluminum, in an inert solvent (e.g.,dimethyl sulfoxide, tetrahydrofuran, ether, dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably from 0° C. to room temperature, to give compound 43.

Compound 41 used as a starting material can be synthesized by Process E,F or 6.

[Process 10]

Compound 45 or 46 can be synthesized in the following manner. Compound45 can be synthesized from compound 44 by Jones oxidation, PCCoxidation, Swern oxidation, or ruthenium oxidation (e.g., TPAP) of the17-hydroxyl group. Compound 45 is further reacted with R₈-M, in which R₈represents a lower alkyl group or a lower alkenyl group or a loweralkynyl group and M represents a metal such as lithium, sodium,potassium, magnesium, calcium or aluminum, in an inert solvent (e.g.,dimethyl sulfoxide, tetrahydrofuran, ether, dimethylformamide) at atemperature ranging from −78° C. to the boiling point of the reactionmixture, preferably from 0° C. to room temperature, to give compound 46.

Compound 44 used as a starting material can be synthesized by Process A,B, C or D.

[Process 11]

Compound 53 can be synthesized in the following manner.

Compound 47 is subjected to protection of its hydroxyl groups, and thenoxidized between 9- and 11-position using DDQ(2,3-dichloro-5,6-dicyanobenzoquinone) and the like to give compound 48.

Compound 48 is converted into compound 49 by the method described in J.Org. Chem., 1995, 60, 5316–5318.

Compound 49 is subjected to Swern oxidation, Jones oxidation, PCCoxidation, or ruthenium oxidation (e.g., TPAP) to give compound 50.

Compound 50 is reacted with an organometallic reagent (e.g.,allylmagnesium halide) in an inert solvent (e.g., tetrahydrofuran,ether) at a temperature ranging from −78° C. to the boiling point of thereaction mixture, preferably from −48° C. to room temperature, to givecompound 51.

Compound 51 is dehydrated to remove its hydroxyl group using thionylchloride/pyridine and the like to give compound 52.

Compound 52 can be converted into compound 53 by Process A, B, C or D.

[Process 12]

Compound 55 can be synthesized by subjecting compound 54 to reactionsanalogous to Process 3. Compound 54 can be synthesized according todocumented methods (Drugs Future, 1978, 3, 211–215; J. Med. Chem., 1967,10, 78–84; J. Med. Chem., 1998, 41, 2928–2931).

[Process 13]

Compound 56 can be converted into compound 57 by the following steps: 1)1,2-addition with X—Mg—(CH₂)_(m)OR₁₂, 2) dehydration, 3) reduction and4) deprotection (R₁₂), and then subjected to reactions analogous toScheme E to give compound 58.

[Process 14]

In the presence of a catalyst such asbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound 59 isreacted with chiral olefin 60 in a solvent (e.g., methylene chloride,chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethylsulfoxide or dimethylformamide) at a temperature ranging from −78° C. tothe boiling point of the reaction mixture, preferably at the boilingpoint of the reaction mixture, to give compound 61. Compound 61 is thensubjected to the following reactions in the order stated, (a) reduction,deprotection and hydrolysis or (b) reduction, hydrolysis anddeprotection, to give compound 62.

(a) Reduction, Deprotection and Hydrolysis

-   1) Reduction

In the presence of a catalyst (e.g., palladium on activated carbon,palladium hydroxide, platinum oxide or Wilkinson's catalyst), compound61 is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethylacetate, tetrahydrofuran, dioxane or benzene) at a temperature rangingfrom 0° C. to the boiling point of the reaction mixture, preferably atroom temperature, to give a reduction product.

-   2) Deprotection

Next, deprotection of the phenolic hydroxyl group is carried out to givea deprotected product.

-   3) Hydrolysis

By way of example, if R* is a group of formula 63, the deprotectedproduct is further treated with lithium hydroxide, sodium hydroxide,lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogenperoxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in asolvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/watermixture, a dioxane/water mixture, a dimethoxyethane/water mixture, amethanol/water mixture, an ethanol/water mixture) at a temperatureranging from room temperature to the boiling point of the reactionmixture, preferably at room temperature, to give compound 62.

(b) Reduction, Hydrolysis and Deprotection

-   1) Reduction

In the presence of a catalyst (e.g., palladium on activated carbon,palladium hydroxide, platinum oxide or Wilkinson's catalyst), compound61 is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethylacetate, tetrahydrofuran, dioxane or benzene) at a temperature rangingfrom 0° C. to the boiling point of the reaction mixture, preferably atroom temperature, to give a reduction product.

-   2) Hydrolysis

By way of example, if R* is a group of formula 63, the reduced productis further treated with lithium hydroxide, sodium hydroxide, lithiumhydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogenperoxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in asolvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/watermixture, a dioxane/water mixture, a dimethoxyethane/water mixture, amethanol/water mixture, an ethanol/water mixture) at a temperatureranging from room temperature to the boiling point of the reactionmixture, preferably at room temperature, to give a carboxylic acid.

-   3) Deprotection

Next, deprotection of the phenolic hydroxyl group is carried out to givecompound 62.

The chiral olefin of formula 60 used in the above process can besynthesized as shown in Reaction Scheme 15.

[Process 15]

[Synthesis of Chiral Olefin]

In the presence of a base (e.g., lithium diisopropylamide, lithiumhexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) andHMPA, compound 67 is reacted with R₂(CH₂)_(n)-L₁ in an inert solvent(e.g., tetrahydrofuran, toluene, diethyl ether, hexane, preferablytetrahydrofuran) at a temperature ranging from −78° C. to the boilingpoint of the reaction mixture, preferably from −30° C. to roomtemperature, to give compound 60.

Chiral olefin 60 can also be synthesized in the following manner.

In the presence of a base (e.g., lithium diisopropylamide, lithiumhexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) andHMPA, compound 68 is reacted with compound 69 in an inert solvent (e.g.,tetrahydrofuran, toluene, diethyl ether, hexane, preferablytetrahydrofuran) at a temperature ranging from −78° C. to the boilingpoint of the reaction mixture, preferably from −30° C. to roomtemperature, to give compound 60.

[Process 16]

Compound 70 can be converted into compound 73 by a procedure analogousto Process 14.

[Process 17]

Compound 75 having substituents R₂₁, R₂₂, R₂₃ and R₂₄ on its benzenering can be converted into compound 77 by a procedure analogous toProcess G. Each of R₂₁, R₂₂, R₂₃ and R₂₄ independently represents ahydrogen atom, a linear or branched C₁–C₅ alkyl group, a linear orbranched C₁–C₇ halogenoalkyl group, a halogen atom or an acyl group.

[Process 18]

Compound 78 is reacted with compound 79 in the presence of a base togive compound 80. Compound 81 can be synthesized from compound 80according to Processes 3 and K.

[Process 19]

Compound 82 synthesized according to the method described in J. Chem.,1057(1984) is subjected to Friedel-Craft reaction with compound 83 andthen treated according to Process 3.

EXAMPLES

The invention is more specifically explained by the following examples.However, it should be understood that the present invention is notlimited to these example in any manner. In order to explain theeffectiveness of the compounds according to the present invention,representative compounds were tested for their anti-estrogenic activityin the test example shown below. Table 1 shows chemical structures ofthe compounds prepared in the Examples.

TABLE 1 Example No. Chemical structure  3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

Example 1 Synthesis of6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene

(Step 1)

6-Methoxy-2-naphthol (22.1 g, 127.0 mmol) was dissolved in acetone (200ml). Potassium carbonate (70.2 g, 508.0 mmol) and allyl bromide (16.5ml, 191.0 mmol) were added to the resulting solution followed bystirring for 2 days at room temperature. After the reaction mixture wasfiltered, the organic solvent was distilled off under reduced pressure.Water was added to the residue, which was then extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride and dried over anhydrous sodium sulfate. The organic solventwas distilled off again to give 6-methoxy-2-(2-propenyloxy)naphthalene(24.9 g, Yield 91%) as a crude product.

¹H-NMR(270 MHz, CDCl₃): δ 7.66–7.60 (m, 2H, Ar—H), 7.18–7.10 (m, 4H,Ar—H), 6.20–6.05 (m, 1H, CH₂═CHCH₂—), 5.45 (dd, J=18.8, 1.3 Hz, 1H, CH₂═CHCH₂—), 5.31 (dd, J10.5, 1.3 Hz, 1H, CH ₂═CHCH₂—), 4.62 (d, J=5.3 Hz,2H, CH₂═CHCH ₂—), 3.90 (s, 3H, —OCH₃).

(Step 2)

6-Methoxy-2-(2-propenyloxy)naphthalene (24.9 g, 116.2 mmol) wasdissolved in N,N-dimethyl aniline (100 ml) followed by heating underreflux for 15 hours. After the organic solvent was distilled off underreduced pressure, 2N aqueous hydrochloric acid was added to the residue,which was then extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride and dried over anhydroussodium sulfate. After distilling off the solvent, the residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=1/4), followed by recrystallization from ethylacetate/hexane, to give 6-methoxy-1-(2-propenyl)-2-naphthol (20.3 g,Yield 82%).

¹H-NMR(270 MHz, CDCl₃): δ 7.80 (d, J=9.3 Hz, 1H, Ar—H), 7.56 (d, J=8.9Hz, 1H, Ar—H), 7.16 (dd, J=9.3, 2.7 Hz, 1H, Ar—H), 7.11 (d, J=2.7 Hz,1H, Ar—H), 7.07 (d, J=8.9 Hz, 1H, Ar—H), 6.13–5.98 (m, 1H, CH₂═CHCH₂—),5.10 (dd, J=10.0, 1.3 Hz, 1H, CH ₂═CHCH₂—), 5.04 (dd, J=17.5, 1.3 Hz,1H, CH ₂═CHCH₂—), 4.93 (s, 1H, —OH), 3.90 (s, 3H, —OCH₃), 3.79 (d, J=5.9Hz, 2H, CH₂═CHCH ₂—).

(Step 3)

6-Methoxy-1-(2-propenyl)-2-naphthol (18.77 g, 87.6 mmol) was dissolvedin dichloromethane (300 ml). To this solution, pyridine (21.3 ml, 262.8mmol) and trifluoromethanesulfonic anhydride (22.1 ml, 131.4 mmol) wereadded dropwise at 0° C., and the resulting mixture was stirred for 30minutes. After the reaction was completed, water was added at 0° C. tothe reaction mixture, which was then extracted with ethyl acetate. Theorganic layer was washed with dilute hydrochloric acid and saturatedaqueous sodium chloride, and then dried over anhydrous sodium sulfate.After distilling off the solvent, the residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/9) to give6-methoxy-1-(2-propenyl)-2-naphthyl trifluoromethanesulfonate (30.8 g,Yield 100%).

¹H-NMR(270 MHz, CDCl₃): δ 7.95 (d, J=9.3 Hz, 1H, Ar—H), 7.69 (d, J=8.9Hz, 1H, Ar—H), 7.35 (d, J=8.9 Hz, 1H, Ar—H), 7.25 (dd, J=9.3, 2.7 Hz,1H, Ar—H), 7.17 (d, J=2.7 Hz, 1H, Ar—H), 6.07–5.94 (m, 1H, CH₂═CHCH₂—),5.10 (dd, J=10.0, 1.3 Hz, 1H, CH ₂═CHCH₂—), 5.02 (dd, J=17.2, 1.3 Hz,1H, CH ₂═CHCH₂—), 3.93 (s, 3H, —OCH₃), 3.89 (d, J=5.6 Hz, 2H, CH₂═CHCH₂—).

(Step 4)

4-Methoxyphenylboronic acid (10.15 g, 66.8 mmol), tripotassium phosphatehydrate (77.6 g, 278.3 mmol) andtetrakis(triphenylphosphine)palladium(0)(1.93 g, 1.67 mmol, 3 mol %)were added to a solution of 6-methoxy-1-(2-propenyl)-2-naphthyltrifluoromethanesulfonate (19.3 g, 55.66 mmol) in dioxane (300 ml),followed by heating under reflux for 8 hours under argon atmosphere.Water was added to the reaction mixture, which was then extracted withethyl acetate, washed with saturated aqueous sodium chloride, and driedover anhydrous sodium sulfate. After distilling off the solvent, theresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/9), followed by recrystallization from hexane, to give6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene (12.65 g, Yield75%).

¹H-NMR(270 MHz, CDCl₃): δ 7.95 (d, J=9.8 Hz, 1H, Ar—H), 7.65 (d, J=8.5Hz, 1H, Ar—H), 7.35 (d, J=8.9 Hz, 1H, Ar—H), 7.34–7.16 (m, 4H, Ar—H),6.96 (d, J=8.6 Hz, 2H, Ar—H), 6.16–6.02(m, 1H, CH₂═CHCH₂—), 5.06 (dd,J=10.2, 1.6 Hz, 1H, CH ₂═CHCH₂—), 4.83 (dd, J=17.2, 1.6 Hz, 1H, CH₂═CHCH₂—), 3.94 (s, 3H, —OCH₃), 3.87 (s, 3H, —OCH₃), 3.73 (d, J=5.3 Hz,2H, CH₂═CHCH ₂—).

Example 2 Synthesis of diethyl2-(5-hexenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate

A solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (4.0 g,12.5 mmol) in dimethyl sulfoxide (30 ml) was cooled to 10° C. To thissolution, 60% sodium hydride (600 mg, 15 mmol) was added, and theresulting mixture was stirred for 1 hour at room temperature.6-Bromo-1-hexene (2.5 ml, 18.75 mmol) was slowly added dropwise to thereaction mixture, followed by stirring for 3 hours at room temperature.Water was added to the reaction mixture, which was then extracted withethyl acetate. The organic layer was washed with water and saturatedaqueous sodium chloride, and then dried over anhydrous sodium sulfate.After distilling off the solvent, the residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/9) to give diethyl2-(5-hexenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate (3.86 g, Yield77%).

¹H-NMR(270 MHz, CDCl₃): δ 5.82–5.72 (m, 1H, —CH═CH₂), 5.02–4.92 (m, 2H,—CH═CH ₂), 4.19 (q, J=7.3 Hz, 4H, —CO₂CH ₂CH₃), 2.10–1.86 (m, 8H),1.53–1.34 (m, 6H), 1.26 (t, J=7.3 Hz, 6H, —CO₂CH₂CH ₃).

Example 3 Synthesis of9-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoicacid

(Step 1)

The diethyl 2-(5-hexenyl)-2-(4,4,5,5,5-pentafluoropentyl)-malonateprepared in Example 2 (1.83 g, 4.55 mmol) andbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium (94 mg, 0.11mmol) were added to a solution of6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene (692 mg, 2.28mmol) in dichloromethane (10 ml), followed by heating under reflux for20 hours under argon atmosphere. After distilling off the solvent, theresidue was purified by silica gel flash column chromatography (eluent:hexane/ethyl acetate=10/1) to give the desired olefin (1.8 g) as amixture of cis- and trans-forms and side chain dimer. This mixture wasdissolved in ethyl acetate (20 ml), and 10% palladium carbon (236 mg)was added to the resulting solution followed by stirring for 2 hours atroom temperature under hydrogen atmosphere. The catalyst was removed byfiltration and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel flash column chromatography (eluent:hexane/ethyl acetate=4/1) to give diethyl2-[7-[6-methoxy-2-(4-methoxyphenyl)napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate(1.05 g, Yield 68%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.96 (d, J=9.3 Hz, 1H, Ar—H), 7.59 (d, J=8.2Hz, 1H, Ar—H), 7.30–7.21 (m, 4H, Ar—H), 7.18–7.15 (m, 1H, Ar—H), 6.97(d, J=8.6 Hz, 2H, Ar—H), 4.18 (q, J=7.0 Hz, 4H, —CO₂CH ₂CH₃), 3.94 (s,3H, —OCH₃), 3.88 (s, 3H, —OCH₃), 2.97–2.91 (m, 2H, naphtyl-CH₂—),2.09–2.03 (m, 2H, —CH ₂CF₂), 1.99–1.82 (m, 4H, alkyl-H), 1.55–1.45(m,6H, alkyl-H), 1.23(t, J=7.0 Hz, 6H, —CO₂CH₂CH ₃), 1.10–1.04(m, 6H,alkyl-H).

(Step 2)

Diethyl2-[7-[6-methoxy-2-(4-methoxyphenyl)napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate(1.02 g, 1.5 mmol) was dissolved in ethanol (10 ml). To this solution,sodium hydroxide (1.2 g, 30 mmol) and water (1 ml) were added, and theresulting mixture was heated under reflux for 3 hours. Dilutehydrochloric acid was added to the reaction mixture, which was thenextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate. The solvent was distilled off to give2-[7-[6-methoxy-2-(4-methoxyphenyl)napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)malonicacid (1.0 g).

Next, the resulting2-[7-[6-methoxy-2-(4-methoxyphenyl)napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)-malonicacid (1.0 g) was dissolved in dimethyl sulfoxide (10 ml) and the mixturewas heated for 4 hours at 120° C. Water was added to the reactionmixture, which was then extracted with ethyl acetate. The organic layerwas washed with saturated aqueous sodium chloride and dried overanhydrous sodium sulfate. After distilling off the solvent, the residuewas purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/1) to give9-[6-methoxy-2-(4-methoxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoicacid (820 mg, Yield 94%).

¹H-NMR(270 MHz, CDCl₃): δ 7.97 (d, J=8.9 Hz, 1H, Ar—H), 7.59 (d, J=8.2Hz, 1H, Ar—H), 7.30–7.21 (m, 4H, Ar—H), 7.18–7.15 (m, 1H, Ar—H), 6.97(d, J=8.6 Hz, 2H, Ar—H), 3.94 (s, 3H, OCH₃), 3.88 (s, 3H, —OCH₃),2.97–2.91 (m, 2H, naphtyl-CH₂—), 2.38–2.35(m, 1H, —CHCO₂), 2.09–1.94 (m,2H, —CH₂CF₂), 1.73–1.41(m, 8H, alkyl-H), 1.29–1.18(m, 8H, alkyl-H).

(Step 3)

A solution of boron tribromide in dichloromethane (1.0 M, 8.5 ml, 8.47mmol) was added dropwise to a solution of9-[6-methoxy-2-(4-methoxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoicacid (820 mg, 1.41 mmol) in dichloromethane (20 ml) at −78° C. underargon atmosphere. The reaction mixture was warmed with stirring to 0° C.over 5 hours. Water was added to the reaction mixture, which was thenextracted with ethyl acetate. The organic layer was washed with waterand saturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After distilling off the solvent, the residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=3/2), followed by column chromatography on reversed-phasesilica gel RP-18 (eluent: acetonitrile containing 0.1% trifluoroaceticacid/water=3/2), to give9-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoicacid (633 mg, Yield 81%).

¹H-NMR(270 MHz, CD₃OD): δ 7.93 (d, J=9.9 Hz, 1H, Ar—H), 7.47 (d, J=8.2Hz, 1H, Ar—H), 7.18–7.11 (m, 5H, Ar—H), 6.85 (d, J=9.3 Hz, 2H, Ar—H),2.97–2.91 (m, 2H, naphtyl-CH₂—), 2.34–2.29 (m, 1H, —CHCO₂), 2.20–1.99(m, 2H, —CH ₂CF₂), 1.62–1.41 (m, 6H, alkyl-H), 1.27–1.18 (m, 10H,alkyl-H).

Example 4 Synthesis of11-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid

The same procedures as shown in Examples 1, 2 and 3 were repeated togive11-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid.

¹H-NMR (270 MHz, CDCl₃): δ 7.98(d, 1H), 7.54(d, 1H), 7.33–7.03(m, 5H),6.88(d, 2H), 2.93(t, 2H), 2.5(m, 1H), 2.2–1.0(m, 22H)

Example 5 Synthesis of10-[(1RS,2RS)-6-hydroxy-2-(4-hydroxyphenyl)-2-methyl-1,2,3,4-tetrahydro-1-naphthyl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid

(Step 1)

6-Methoxy-2-(4-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydro-naphthalen-1-onewas synthesized by the method described in U.S. Pat. No. 4,904,661. Asolution of this compound (1.5 g, 5.1 mmol) as dissolved in anhydroustetrahydrofuran (25 ml) was added dropwise to a solution of lithiumaluminum hydride in anhydrous tetrahydrofuran (1M in THF, 2.6 ml, 2.6mmol) at −78° C. under argon atmosphere. The reaction was continued for1.5 hours. The reaction mixture was then warmed slowly to roomtemperature and stirred for 8 hours. Saturated aqueous ammonium chloridewas added to the reaction mixture, which was then extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumbicarbonate, water and saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, and then evaporated to remove the solvent.The resulting residue was dissolved in 1,2-dichloroethane (35 ml). Tothis solution, zinc iodide (2.02 g, 6.31 mmol) and allyltrimethylsilane(1.67 ml, 10.52 mmol) were added at 0° C. under argon atmosphere, andthe resulting mixture was stirred for 12 hours at room temperature.Water was added to the reaction mixture, which was then extracted withdichloromethane. The organic layer was washed with saturated aqueoussodium bicarbonate, water and saturated aqueous sodium chloride, andthen dried over anhydrous magnesium sulfate. After distilling off thesolvent, the residue was purified by silica gel flash columnchromatography (eluent: hexane/ethyl acetate=60/1) to give(1RS,2RS)-6-methoxy-2-(4-methoxyphenyl)-2-methyl-1-(2-propenyl)-1,2,3,4-tetrahydronaphthalene(1.27 g, Yield 78%).

¹H-NMR (300 MHz, CDCl₃): δ 7.31(d, 2H, J=7.5 Hz), 6.97(d, 1H, J=7.9 Hz),6.88(d, 2H, J=8.7 Hz), 6.68–6.65(m, 2H), 5.53(m, 1H), 4.76–4.57(m, 2H),3.81(s, 3H), 3.78(s, 3H), 2.99–2.78(m, 2H), 2.81(m, 1H), 2.28(m, 1H),1.98–1.92(m, 2H), 1.71(m, 1H), 1.17(s, 3H).

(Step 2)

The(1RS,2RS)-6-methoxy-2-(4-methoxyphenyl)-2-methyl-1-(2-propenyl)-1,2,3,4-tetrahydronaphthalenethus prepared was converted into10-[(1RS,2RS)-6-hydroxy-2-(4-hydroxyphenyl)-2-methyl-1,2,3,4-tetrahydro-1-naphthyl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid by a procedure analogous to Example 3.

¹H-NMR (300 MHz, CDCl₃): δ 7.23(d, 2H, J=7.5 Hz), 6.90(d, 1H, J=7.9 Hz),6.80(d, 2H, J=8.7 Hz), 6.58(m, 2H), 2.90(m, 2H), 2.60(d, 1H, J=8.7 Hz),2.37(m, 1H), 2.22(m, 1H), 2.02(m, 2H), 1.87(m, 1H), 1.37–1.75(m, 6H),0.86–1.26(m, 17H).

Mass (ESI): 585(M+1).

Example 6 Synthesis of2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-6,6,7,7,7-pentafluoroheptanoicacid

(Step 1)

4-Methoxybenzoic acid (450 mg, 2.96 mmol), thionyl chloride (3 ml, 44.4mmol) and anhydrous dimethylformamide (1 drop) were added to anhydrouschloroform (10 ml), and the resulting mixture was refluxed for 3 hoursunder argon atmosphere and then cooled to room temperature. After thereaction mixture was concentrated under reduced pressure, the residuewas dissolved in anhydrous dichloromethane, and6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (760 mg, 2.8 mmol)synthesized by the method described in J. Med. Chem. 1057(1984) andaluminum chloride (2.37 g, 17.76 mmol) were added to the resultingsolution followed by stirring for 4 hours at room temperature.Tetrahydrofuran and ice were added to stop the reaction and the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated aqueous sodium chloride, and then dried overanhydrous magnesium sulfate. After distilling off the solvent, thefiltrate was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography (eluent:dichloromethane/hexane=1/1) to give[6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-methoxy-phenyl)-methanone(405 mg, Yield 39%) as a yellow oil.

¹H-NMR(300 MHz, CDCl₃): δ 7.80–7.75 (m, 2H), 7.52 (d, 1H, J=8.6 Hz),7.37–7.28 (m, 3H), 6.95 (dd, 1H, J₁=8.9 Hz, J₂=2.2 Hz), 6.78–6.74 (m,4H), 3.91 (s, 3H), 3.85 (s, 3H), 3.77 (s, 3H).

(Step 2)

[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-methoxyphenyl)methanone(410 mg, 1.02 mmol) was dissolved in anhydrous dimethylformamide (15ml), and sodium ethanethiolate (170 mg, 2.04 mmol) was added to theresulting solution followed by stirring for 1.5 hours at a temperatureof 90° C. to 100° C. under argon atmosphere. The reaction mixture wascooled to room temperature and, after addition of water, was extractedwith ethyl acetate. The organic layer was washed with water andsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After distilling off the solvent, the residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=1/1) to give(4-hydroxyphenyl)[6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]methanone(323 mg, Yield 81.6%) as a yellow oil.

¹H-NMR(300 MHz, CDCl₃): δ 7.70 (d, 2H, J=9.0), 7.51 (d, 1H, J=8.7),7.33–7.26 (m, 3H), 6.95 (dd, 1H, J₁=8.9 Hz, J₂=2.6 Hz), 6.75–6.65 (m,4H), 3.87 (s, 3H), 3.72 (s, 3H).

(Step 3)

Diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (3 g, 9.37 mmol) wasdissolved in dimethyl sulfoxide (20 ml), and sodium hydride (60%, 525mg, 13.11 mmol) was added to the resulting solution followed by stirringfor 1 hour at room temperature. 5-Bromo-1-chloropentane (7.4 ml, 56.2mmol) was added to the reaction mixture, followed by stirring for 1.5hours at room temperature. The reaction mixture was diluted with water,extracted with ethyl acetate, washed with water and saturated aqueoussodium chloride, and then dried over anhydrous magnesium sulfate. Thefiltrate was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography (eluent:dichloromethane/hexane=1/4) to give diethyl2-(5-chloropentyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate (3.3 g, Yield83%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 4.14 (q, 4H, J=7.1 Hz), 3.46(t, 2H, J=6.7Hz), 2.06–1.64(m, 8H), 1.50–1.36(m, 4H), 1.24–1.10(m, 2H), 1.21(t, 6H,J=7.1 Hz).

(Step 4)

(4-Hydroxyphenyl)[6-methoxy-2-(4-methoxyphenyl)benzo-[b]thiophen-3-yl]methanone(1 g, 2.56 mmol) was dissolved in dimethylformamide (15 ml), and sodiumhydride (60%, 143 mg, 3.59 mmol) was added to the resulting solutionfollowed by stirring for 1 hour at room temperature.

Diethyl 2-(5-chloropentyl)-2-(4,4,5,5,5-pentafluoropentyl)-malonate(1.85 g, 4.35 mmol), sodium iodide (769 mg, 5.13 mmol) andtetrabutylammonium iodide (189 mg, 0.51 mmol) were added to the reactionmixture followed by stirring for 24 hours at 60° C. After the reactionmixture was cooled to room temperature, saturated aqueous ammoniumchloride was added to the reaction mixture, which was then extractedwith ethyl acetate, dried over anhydrous magnesium sulfate and filtered.The filtrate was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/9) to give diethyl2-[5-[4-[(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)-carbonyl]-phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate(1.4 g, Yield 70%) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃): δ 7.73(d, 2H, J=9.1 Hz), 7.48(d, 1H, J=8.5 Hz),7.32(d, 2H, J=8.6 Hz), 7.27(d, 1H, J=2.3 Hz), 6.91(dd, 1H, J₁=8.8 Hz,J₂=2.3 Hz), 6.74–6.67(m, 4H), 4.15(q, 4H, J=7.1 Hz), 3.88(t, 2H, J=6.3Hz), 3.83(s, 3H), 3.70(s, 3H), 2.08–1.82(m, 6H), 1.75–1.71(m, 2H),1.53–1.37(m, 6H), 1.21(t, 6H, J=7.1 Hz).

(Step 5)

Diethyl2-[5-[4-[(6-methoxy-2-(4-methoxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate(1.58 g, 2.03 mmol) was dissolved in dichloromethane (40 ml), andaluminum chloride (1.62 g, 12.2 mmol) and ethanethiol (0.25 ml, 10.15mmol) were added to the resulting solution followed by stirring for 1.5hours at room temperature. After the reaction mixture was cooled to 0°C., tetrahydrofuran (30 ml) was slowly added to the reaction mixture,which was then diluted with water and extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, and then filtered. The filtrate wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=1/2) to give diethyl2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate(1.2 g, Yield 79%) as a brown foam.

¹H-NMR (300 MHz, CDCl₃): δ 7.73(d, 2H, J=9.1 Hz), 7.38(d, 1H, J=8.6 Hz),7.18(d, 1H, J=2.3 Hz), 7.14(d, 2H, J=8.6 Hz), 6.79(dd, 1H, J₁=8.6 Hz,J₂=2.3H), 6.72(d, 2H, J=9.1 Hz), 6.57(d, 2H, J=8.6 Hz), 4.17(q, 4H,J=7.2 Hz), 3.91(t, 2H, J=6.1 Hz), 2.10–1.78(m, 6H), 1.74–1.68(m, 2H),1.54–1.36(m, 4H), 1.26–1.13 (m, 2H), 1.21(t, 6H, J=7.2 Hz).

(Step 6)

Diethyl2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonate(1.197 g, 1.59 mmol) was dissolved in ethanol (20 ml), and potassiumhydroxide (3.58 g, 63.8 mmol) dissolved in water (10 ml) was then added.After stirring for 24 hours at 80° C., the reaction mixture was cooledto room temperature, concentrated under reduced pressure to removeethanol, adjusted to pH 3 with 3N aqueous hydrochloric acid, and thenextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated underreduced pressure to give2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonicacid (1.1 g) as a brown product, which was then used for the subsequentreaction without further purification.

¹H-NMR (300 MHz, CD₃OD): δ 7.68(d, 2H, J=9.0 Hz), 7.38(d, 1H, J=9.0 Hz),7.24(d, 1H, J=2.0 Hz), 7.18(d, 2H, J=8.6 Hz), 6.85(dd, 1H, J₁=9.0 Hz,J₂=2.0 Hz), 6.80(d, 2H, J=8.6 Hz), 6.63(d, 2H, J=8.6 Hz), 3.95(t, 2H,J=6.0 Hz), 2.21–1.80(m, 6H), 1.74–1.70(m, 2H), 1.58–1.21(m, 6H).

(Step 7)

2-[5-[4-[(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]-phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonicacid (1.1 g, 1.58 mmol) was dissolved in dimethyl sulfoxide (10 ml) andstirred for 3 hours at 120° C. The reaction mixture was cooled to roomtemperature, diluted with water, and then extracted with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was concentrated under reduced pressure and theresulting residue was purified by silica gel column chromatography(eluent: ethyl acetate/hexane=1/1) to give2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-6,6,7,7,7-pentafluoroheptanoicacid (732 mg, Yield 71%) as a yellow solid.

¹H-NMR (300 MHz, CD₃OD): δ 7.68(d, 2H, J=8.8 Hz), 7.38(d, 1H, J=8.8 Hz),7.25(d, 1H, J=2.3 Hz), 7.18(d, 2H, J=8.6 Hz), 6.85(dd, 1H, J₁=8.8 Hz,J₂=2.3 Hz), 6.79(d, 2H, J=8.9 Hz), 6.63(d, 2H, J=8.6 Hz), 3.95(t, 2H,J=6.5 Hz), 2.85(m, 1H), 2.15–1.94(m, 2H), 1.78–1.29(m, 12H).

Mass (ESI): 651(M+1).

Example 7 Synthesis of8-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]-2-(4,4,5,5,5-pentafluoropentyl)octanoicacid

The same procedure as shown in Example 1 was repeated to give8-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]-2-(4,4,5,5,5-pentafluoropentyl)octanoicacid.

¹H-NMR(300 MHz, CDCl₃): δ 7.68 (d, 2H, J=8.6 Hz), 7.38 (d, 1H, J=8.7Hz), 7.24–7.16 (m, 3H), 6.86–6.78 (m, 3H), 6.62 (d, 2H, J=8.3 Hz), 3.95(t, 2H, J=6.4 Hz), 2.35 (m, 1H), 2.15–1.95 (m, 2H), 1.77–1.25 (1m, 4H).

Mass(ESI): 665 (M+1).

Example 8 Synthesis of2-[2-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]-phenoxy]ethyl]-6,6,7,7,7-pentafluoroheptanoicacid

The same procedure as shown in Example 1 was repeated to give2-[2-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]ethyl]-6,6,7,7,7-pentafluoroheptanoicacid.

¹H-NMR (300 MHz, CDCl₃+CD₃OD): δ 7.70(d, 2H, J=8.9 Hz), 7.50(d, 1H,J=8.8 Hz), 7.26(d, 1H, J=2.2 Hz), 7.20(d, 2H, J=8.6 Hz) 6.90 (dd, 1H,J₁=8.8 Hz, J₂=2.2 Hz), 6.70(d, 2H, J=8.9 Hz), 6.65(d, 2H, J=8.6 Hz),4.10–3.90(m, 2H), 2.58(m, 1H), 2.18–1.84(m, 4H), 1.82–1.52(m, 4H).

Example 9 Synthesis of2-[3-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]-phenoxy]propyl]-6,6,7,7,7-pentafluoroheptanoicacid

The same procedure as shown in Example 1 was repeated to give2-[3-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]propyl]-6,6,7,7,7-pentafluoroheptanoicacid.

¹H-NMR (300 MHz, CDCl₃): δ 7.73(d, 2H, J=8.8 Hz), 7.47(d, 1H, J=8.8 Hz),7.27(d, 1H, J=2.2 Hz), 7.21(d, 2H, J=8.6 Hz), 6.86(dd, 1H, J₁=8.7 Hz,J₂=2.3 Hz), 6.73(d, 2H, J=8.9 Hz), 6.67(d, 2H, J=8.6 Hz), 3.94(t, 2H,J=6.1 Hz), 2.39(m, 1H), 2.10–1.97(m, 2H), 1.82–1.55(m, 8H).

Mass(ESI): 623 (M+1)

Example 10 Synthesis of2-[4-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophen-3-yl)carbonyl]phenoxy]butyl]-6,6,7,7,7-pentafluoroheptanoicacid

The same procedure as shown in Example 1 was repeated to give2-[4-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]butyl]-6,6,7,7,7-pentafluoroheptanoicacid.

¹H-NMR(300 MHz, CDCl₃): 7.71 (d, 2H, J=8.8 Hz), 7.54(d, 1H, J=8.7 Hz),7.26(d, 1H, J=2.3 Hz), 7.19(d, 2H, J=8.6 Hz), 6.88(dd, 1H, J₁=8.8 Hz,J₂=2.3 Hz), 6.69(d, 2H, J=8.8 Hz), 6.64(d, 2H, J=8.6), 3.93(t, 2H, J=6.1Hz), 2.38(m, 1H), 2.15–1.47(m, 12H).

Mass(ESI): 637 (M+1).

Example 11 Synthesis of10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid

(Step 1)

Thionyl chloride (0.65 ml) was added to (R)-4-hydroxyphenylglycine (1.00g, 5.98 mmol) in methanol (10 ml), followed by stirring overnight atroom temperature. The reaction mixture was concentrated under reducedpressure and the residue was dissolved in ethyl acetate (20 ml).Saturated aqueous sodium bicarbonate (20 ml) anddi-tert-butyl-dicarbonate (1.57 g, 7.19 mmol) were added to theresulting solution followed by stirring for 4 hours at room temperature.After the reaction mixture was separated into organic and aqueouslayers, the organic layer was washed sequentially with water andsaturated aqueous sodium chloride, and then dried over anhydrous sodiumsulfate. After the organic layer was concentrated under reducedpressure, the resulting solids were washed with ethyl acetate/hexane togive (R)-N-(tert-butoxycarbonyl)-4-hydroxyphenylglycine methyl ester(1.47 g, Yield 87%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.18(2H, d, J=8.6 Hz), 6.74(2H, d, H=8.6 Hz),5.71(1H, brs), 5.50–5.60(1H, m), 5.18–5.26(1H, m), 3.71(3H, s), 1.43(9H,s)

(Step 2)

Benzyl bromide (0.66 ml, 5.55 mmol) was added to(R)-(N-tert-butoxycarbonyl)-4-hydroxyphenylglycine methyl ester (1.42 g,5.05 mmol) and potassium carbonate (768 mg, 5.56 mmol) in acetone (5ml). The resulting mixture was stirred overnight at room temperature andthen heated under reflux for 1 hour. After cooling, the reaction mixturewas concentrated under reduced pressure. Ethyl acetate was added to theresulting residue, which was then washed sequentially with water andsaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate. After the organic layer was concentrated under reducedpressure, the resulting solids were washed with ethyl acetate/hexane togive (R)-N-(tert-butoxycarbonyl)-4-benzyloxyphenylglycine methyl ester(1.67 g, Yield 89%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.30–7.45(5H, m), 7.27(2H, d, J=8.6 Hz),6.95(2H, d, J=8.6 Hz), 6.40–6.55(1H, m), 6.20–6.30(1H, m), 5.05(2H, s),3.71(3H, s), 1.43(9H, s)

(Step 3)

Ethanol (4 ml) was added to(R)-N-(tert-butoxy-carbonyl)-4-benzyloxyphenylglycine methyl ester (200mg, 0.538 mmol) and lithium tetrahydroborate (23 mg, 1.06 mmol) intetrahydrofuran (2 ml), followed by stirring overnight at roomtemperature. The reaction mixture was acidified (pH 4) with 10% citricacid and concentrated under reduced pressure. Ethyl acetate was added tothe resulting residue, which was then washed sequentially with water andsaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate. The organic layer was concentrated under reduced pressure togive (R)-2-(tert-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (187mg, Yield 100%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.27–7.45(5H, m), 7.21(2H, d, J=8.6 Hz),6.96(2H, d, J=8.6 Hz), 5.05–5.20(1H, m), 5.05(2H, s), 5.65–5.80(1H, m),3.75–3.85(2H, m), 2.35(1H, brs), 1.43(9H, s)

(Step 4)

Diisopropylazodicarboxylate (0.10 ml, 0.603 mmol) was added to(R)-2-(tert-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (161 mg,0.469 mmol), 5-benzyloxy-2-bromophenol (131 mg, 0.469 mmol) andtriphenylphosphine (160 mg, 0.610 mmol) in tetrahydrofuran (3 ml) undera nitrogen stream, followed by stirring for 5 hours at room temperature.Diisopropylazodicarboxylate (0.05 ml, 0.302 mmol) was added to thereaction mixture followed by stirring for 3 hours at room temperature.Water was added to the reaction mixture, which was then extracted withethyl acetate. The organic layer was washed sequentially with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and then concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=1/4, v/v) to give(R)-N-(tert-butoxycarbonyl)-2-(5-benzyloxy-2-bromophenoxy)-1(4-benzyloxyphenyl)ethylamine(214 mg, Yield 75%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.25–7.45(13H, m), 6.95(2H, d, J=8.6 Hz),6.40–6.55(2H, m), 5.35–5.50(1H, m), 5.05(2H, s), 5.00(2H, s),4.95–5.05(1H, m), 4.05–4.25(2H, m), 1.42(9H, m)

(Step 5)

Trifluoroacetic acid (1 ml) was added to(R)-N-(tert-butoxycarbonyl)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine(200 mg, 0.331 mmol) in methylene chloride (1 ml), followed by stirringfor 1 hour at room temperature. The reaction mixture was concentratedunder reduced pressure, made basic with saturated aqueous sodiumbicarbonate, and then extracted with ethyl acetate. The organic layerwas washed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=2/1, v/v) to give(R)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (127mg, Yield 76%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.25–7.45(13H, m), 6.97(2H, d, J=8.6 Hz),6.42–6.53(2H, m), 5.07(2H, s), 5.00(2H, s), 4.42(1H, dd, J=8.9, 3.6 Hz),4.07(1H, dd, J=8.9, 3.6 Hz), 3.87(1H, dd, J=8.9, 8.9 Hz), 1.77(2H, brs)

(Step 6)

A solution of(R)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (120mg, 0.238 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (15 mg, 0.024 mmol)and potassium-t-butoxide (37 mg, 0.330 mmol) in toluene (2.5 ml) wasstirred for 3 hours at 100° C. under a nitrogen stream. After cooling,water was added to the reaction mixture, which was then extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/5, v/v) to give(R)-7-benzyloxy-3-(4-benzyloxy-phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine(55.4 mg, Yield 55%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.25–7.50(12H, m), 6.98(2H, d, J=8.6 Hz),6.58(1H, d, J=8.6 Hz), 6.55(1H, d, J=2.6 Hz), 6.48(1H, dd, J=8.6, 2.6Hz), 5.07(2H, s), 4.99(2H, s), 4.39(1H, dd, J=8.9, 2.6 Hz), 4.22(1H, dd,J=10.6, 2.6 Hz), 3.96(1H, dd, 10.6, 8.9 Hz), 3.73(1H, brs)

(Step 7)

A solution of(R)-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine(47.6 mg, 0.112 mmol), sodium iodide (67 mg, 0.450 mmol), potassiumcarbonate (31 mg, 0.224 mmol) and allyl bromide (0.04 ml, 0.473 mmol) inacetone (1 ml) was stirred for 3 hours at 50° C. under a nitrogen streamand then heated under reflux for 7 hours. After cooling, water was addedto the reaction mixture, which was then extracted with ethyl acetate.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluent: ethyl acetate/hexane=1/5, v/v) to give(R)-4-allyl-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine(44 mg, Yield 85%).

¹H-NMR (270 MHz, CDCl₃) δ: 7.25–7.45(10H, m), 7.20(2H, d, J=8.6 Hz),6.95(2H, d, J=8.6 Hz), 6.74(1H, d, J=9.6 Hz), 6.50–6.56(2H, m),5.68–5.85(1H, m), 5.06–5.17(2H, m), 5.05(2H, s), 4.98(2H, s), 4.33(1H,d, J=6.9, 3.0 Hz), 4.19(1H, dd, J=10.9, 3.0 Hz), 4.11(1H, dd, J=10.9,6.9 Hz), 4.85–4.98(1H, m), 3.47(1H, dd, J=16.8, 6.3 Hz)

(Step 8)

1) A solution of(R)-4-allyl-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo-[1,4]oxazine(177 mg, 0.382 mmol), 2-(6,6,7,7,7-pentafluoroheptyl)-non-8-enoic acidethyl ester (285 mg, 0.765 mmol) andbenzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (16 mg, 0.019mmol) in dichloromethane(2 ml) was heated under reflux for 5 hours undera nitrogen stream. The reaction mixture was further mixed with2-(6,6,7,7,7-pentafluoroheptyl)-non-8-enoic acid ethyl ester (71 mg,0.190 mmol) andbenzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (16 mg, 0.019mmol) and then heated under reflux for 2 hours. After cooling, thereaction mixture was concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (eluent:chloroform/hexane=3/1, v/v) to give an oil (197 mg).2) A mixture of the oil prepared in 1) above and 10% Pd—C (13 mg, 0.012mmol) in ethanol/methanol (1:1, 3 ml) was stirred for 13 hours at roomtemperature under a hydrogen stream. After the reaction mixture wasfiltered through cellite, the mother liquid was concentrated underreduced pressure. The resulting residue was subjected to two additionalreduction reactions as stated above. The resulting residue was furtherpurified by silica gel column chromatography (eluent: ethylacetate/hexane=1/2→1/1, v/v) to give ethyl10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo-[1,4]oxazine-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoate(60.2 mg, Yield 26%).

¹H-NMR (270 MHz, CD₃OD) δ: 7.13(2H, d, J=8.6 Hz), 6.78(2H, d, J=8.6 Hz),6.65(1H, d, J=8.6 Hz), 6.36(1H, dd, J=8.6, 2.6 Hz), 6.29(1H, d, J=2.6Hz), 4.27(1H, dd, J=6.3, 3.0 Hz), 4.00–4.20(4H, m), 3.20–3.35(1H, m),2.80–2.95(1H, m), 2.30–2.45(1H, m), 2.00–2.23(2H, m), 1.15–1.70(25H, m)

(Step 9)

Aqueous sodium hydroxide (1N, 1 ml) was added to ethyl10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]-oxazine-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoate(56.8 mg, 0.0902 mmol) in ethanol (1 ml) under a nitrogen stream,followed by stirring for 7 hours at 50° C. After cooling, the reactionmixture was acidified with 1N aqueous hydrochloric acid and extractedwith ethyl acetate. The organic layer was washed sequentially with waterand saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, and then concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/1, v/v) to give10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]-oxazine-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid (41.4 mg, Yield 76%).

¹H-NMR (270 MHz, CD₃OD) δ: 7.13(2H, d, J=8.6 Hz), 6.78(2H, d, J=8.6 Hz),6.64(1H, d, J=8.6 Hz), 6.37(1H, dd, J=8.6, 2.6 Hz), 6.29(1H, d, J=2.6Hz), 4.21–4.35(1H, m), 4.12(1H, dd, J=10.6, 3.0 Hz), 4.05(1H, dd,J=10.6, 6.6 Hz), 3.20–3.35(1H, m), 2.82–2.95(1H, m), 2.25–2.38(1H, m),2.00–2.21(2H, m), 1.10–1.70(22H, m)

Example 12 Synthesis of10-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid

(Step 1)

A solution of 3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11-one (148.8mg, 0.318 mmol) in anhydrous tetrahydrofuran (2.5 ml) was cooled to −10°C. under argon atmosphere. To this solution, a 1.0 M solution of allylmagnesium bromide in anhydrous ether (1.5 ml, 1.5 mmol) was addeddropwise, and the resulting mixture was stirred for 15 hours at roomtemperature. The reaction mixture was cooled to 0° C., followed byaddition of water and saturated aqueous ammonium chloride. After thereaction mixture was extracted with ethyl acetate, the organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and then filtered. After distilling off the solvent,the residue was purified by silica gel flash chromatography (eluent:hexane/ethyl acetate=6/1) to give3,17β-bis(benzyloxy)-11α-(2-propenyl)estra-1,3,5(10)-trien-11β-ol (150.4mg, Yield 93%).

¹H-NMR (270 MHz, CDCl₃): δ 7.79 (d, J=10 Hz, 1H, C1-H), 7.44–7.29 (m,10H), 6.82–6.76 (m, 2H, C2 and C4-H), 6.00–5.85 (m, 1H, olefin-H),5.20–5.12 (m, 2H, olefin-H), 5.04 (s, 2H, Ph—CH₂), 4.55 (s, 2H, Ph—CH₂),3.44 (t, J=8 Hz, 1H, C17-H), 2.88 (dd, J=14, 8 Hz, 1H, allylic-CH₂),2.78–2.58 (m, 2H), 2.50 (dd, J=14, 7 Hz, 1H, allylic-CH₂), 2.23 (d, J=11Hz, 1H), 2.11 (d, J=14 Hz, 1H), 2.08–1.95 (m, 1H), 1.90–1.15 (m, 9H),1.07(s, 3H, C18-H).

(Step 2)

Benzylidenebis(tricyclohexylphosphine)-dichlororuthenium (5.9 mg,0.00717 mmol) was added to a solution of3,17β-bis(benzyloxy)-11α-(2-propenyl)estra-1,3,5(10)-trien-11β-ol (65.5mg, 0.129 mmol) and ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate(101.3 mg, 0.272 mmol) in dichloromethane (0.5 ml), followed by heatingunder reflux for 2.5 hours under argon atmosphere. After cooling, ethyl2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate (100 mg, 0.269 mmol) andbenzylidenebis(tricyclohexylphosphine)-dichlororuthenium (6 mg, 0.00729mmol) were added to the reaction mixture, which was then heated underreflux for 3 hours under argon atmosphere. After cooling, ethyl2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate (100 mg, 0.269 mmol) andbenzylidenebis(tricyclohexylphosphine)-dichlororuthenium (6 mg, 0.00729mmol) were further added to the reaction mixture, which was then heatedunder reflux for 6.5 hours under argon atmosphere and allowed to cool.Apart from this,benzylidenebis(tricyclohexylphosphine)-dichlororuthenium (6.8 mg,0.00826 mmol) was added to a solution of3,17β-bis(benzyloxy)-11α-(2-propenyl)estra-1,3,5(10)-trien-11β-ol (84.5mg, 0.166 mmol) and ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate(124 mg, 0.333 mmol) in dichloromethane (0.5 ml), followed by heatingunder reflux for 2.5 hours under argon atmosphere. After cooling, ethyl2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate (124 mg, 0.333 mmol) andbenzylidenebis(tricyclohexylphosphine)-dichlororuthenium (6.8 mg,0.00826 mmol) were added to the reaction mixture, which was then heatedunder reflux for 3 hours under argon atmosphere. After cooling, ethyl2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate (124 mg, 0.333 mmol) andbenzylidenebis(tricyclohexylphosphine)-dichlororuthenium (6.8 mg,0.00826 mmol) were further added to the reaction mixture, which was thenheated under reflux for 6.5 hours under argon atmosphere and allowed tocool. The thus prepared two reaction mixtures were combined andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography (eluent: hexane/ethyl acetate=5/1) to giveethyl10-[3,17β-bis(benzyloxy)-11β-hydroxyestra-1,3,5(10)-trien-11α-yl]-2-(6,6,7,7,7-pentafluoroheptyl)-8-decenoate(186.4 mg, Yield 74%).

¹H-NMR(270 MHz, CDCl₃): δ 7.79(d, J=100 Hz, 1H), 7.45–7.25(m, 10H),6.82–6.72(m, 2H), 5.62–5.40(m, 2H, olefin-H), 5.04(s, 2H, Ph—CH₂),4.55(s, 2H, Ph—CH₂), 4.13(q, J=7 Hz, 2H, COO—CH₂), 3.42(t, J=8 Hz, 1H),2.95–1.14(m, 40H), 1.07(s, 3H).

(Step 3)

A 30% solution of HBr in acetic acid (2 ml) was added to a solution ofethyl10-[3,17β-bis(benzyloxy)-11β-hydroxyestra-1,3,5(10)-trien-11α-yl]-2-(6,6,7,7,7-pentafluoroheptyl)-8-decenoate(155.4 mg, 0.182 mmol) in ethanol (8 mL), followed by stirring for 24hours at 50° C. After cooling, the reaction mixture was poured intosaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, and then filtered. Afterconcentration under reduced pressure, the resulting residue was purifiedby silica gel flash chromatography (eluent: hexane/ethyl acetate=20/1)to give an oil. This oil was dissolved in a mixed solvent of ethanol (5ml) and methanol (5 ml). 10% palladium carbon (78.8 mg) was added to theresulting solution followed by stirring for 14 hours at room temperatureunder hydrogen atmosphere. After purging with nitrogen, 10% palladiumcarbon (74.0 mg) was added to the reaction mixture, followed by stirringfor 15 hours at room temperature under hydrogen atmosphere. The reactionmixture was filtered and concentrated, the residue was dissolved inmethanol (10 ml). 10% Palladium carbon (80 mg) was added again to thereaction mixture, followed by stirring for 2 days at room temperatureunder hydrogen atmosphere. After the reaction mixture was filtered andconcentrated, the residue was purified by silica gel flashchromatography (eluent: hexane/ethyl acetate=10/1) to give an oil. Thisoil was further purified using a silica gel plate (developing solvent:hexane/ethyl acetate=2/1) to give ethyl10-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoate(14.6 mg, Yield 12%).

¹H-NMR (270 MHz, CDCl₃): δ 7.00(d, J=8.6 Hz, 1H), 6.62(dd, J=8.6, 2.6Hz, 1H), 6.55(d, J=2.6 Hz, 1H), 5.28(bs, 1H, Ar—OH), 4.15(q, J=7.3 Hz,2H, COO—CH₂), 3.70(t, J=8.6 Hz, 1H), 2.90–1.10(m, 45H), 0.91(s, 3H).

Rf value: 0.45 (silica gel plate, developing solvent: hexane/ethylacetate=2/1).

(Step 4)

Ethyl10-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoate(11.1 mg, 0.0168 mmol) was dissolved in a mixed solvent of ethanol (0.5ml) and tetrahydrofuran (0.5 ml). To this solution, 1N aqueous NaOH (0.5ml) was added and the resulting mixture was heated under reflux for 5hours. After cooling, saturated aqueous ammonium chloride was added tothe reaction mixture, which was then extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, and then filtered. After concentrationunder reduced pressure, the resulting residue was purified using asilica gel plate (developing solvent: hexane/ethyl acetate=1/1) to give10-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid (5.3 mg, Yield 50%).

¹H-NMR(270 MHz, CDCl₃): δ 7.00(d, J=8.3 Hz, 1H), 6.62(d, J=8.3 Hz, 1H),6.54(s, 1H), 3.73(t, J=8.1 Hz, 1H), 2.90–1.07(m, 42H), 0.92(s, 3H).

Mass (ESI): 653(M+Na).

Rf value: 0.22 (silica gel plate, developing solvent: hexane/ethylacetate=1/1).

Example 13 Synthesis of11-(3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl)-2-(4,4,5,5,5-penta-fluoropentyl)undecanoicacid

(Step 1)

n-Butyllithium (2.5 M in hexane, 40 ml, 100 mmol) was added to potassiumtert-butoxide (1M in tetrahydrofuran, 100 ml, 100 mmol) at −70° C. undernitrogen atmosphere, followed by addition of diisopropylamine (19.1 g,100 mmol) at the same temperature. After the mixture was stirred for 10minutes, 17β-(t-butyldimethylsiloxy)-3-methoxyestra-1,3,5(10)-triene (10g, 25 mmol) synthesized by the method described in Tetrahedron Lett.,3223 (1988) and dissolved in tetrahydrofuran (40 ml) was added dropwiseat −70° C. over 10 to 15 minutes, and the resulting mixture was stirredfor 4 hours. Trimethyl borate (15.6 g, 150 mmol) was added to thereaction mixture, which was then warmed to ice cold temperature andstirred for 1 hour and further stirred with 30% hydrogen peroxide (35ml) for 1 hour at room temperature. The reaction mixture was cooledagain on ice and 10% aqueous sodium thiosulfate (150 ml) was added tostop the reaction. After the reaction mixture was extracted with ether,the organic layer was washed with water and saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, and then filtered.After distilling off the solvent, the residue was purified by silica gelflash chromatography (eluent: hexane/ethyl acetate=5/1→3/1) to give17β-(t-butyl-dimethylsiloxy)-3-methoxyestra-1,3,5(10)-trien-6-ol (8.38g, Yield 82%).

¹H-NMR(300 MHz, CDCl₃) δ 7.18 (d, J=8.5 Hz, 1H, C1-CH), 7.11 (d, J=2.7Hz, 1H, C4-CH), 6.77 (dd, J=8.5, 2.7 Hz, 1H, C2-CH), 4.8 (m, 1H), 3.78(s, 3H, C3-OCH3), 3.62 (m, 1H), 2.3–2.2 (m, 3H), 2.0–1.8 (m, 2H),1.7–1.1 (m, 8H), 0.87 (s, 9H), 0.71 (s, 3H, C18-CH₃), 0.04 (s, 3H), 0.03(s, 3H).

(Step 2)

17β-(t-Butyldimethylsiloxy)-3-methoxyestra-1,3,5(10)-trien-6-ol (14.4 g,34.5 mmol) was dissolved in dichloromethane (250 ml). Manganese dioxide(29 g) and molecular sieves 4A powder (7.2 g) were added to theresulting solution followed by stirring for 1 hour at room temperature.The reaction mixture was filtered through cellite and the filtrate wasconcentrated under reduced pressure. The residue was recrystallized fromhexane to give17β-(t-butyldimethylsiloxy)-3-methoxyestra-1,3,5(10)-trien-6-one (11.36g, Yield 79%).

¹H-NMR(300 MHz, CDCl₃): δ 7.55 (d, J=3.0 Hz, 1H, C4-CH), 7.34 (d, J=8.5Hz, 1H, C1-CH), 7.10 (dd, J=8.5, 3.0 Hz, 1H, C2-CH), 3.84 (s, 3H,C3-OCH₃), 3.66 (m, 1H), 2.74 (dd, J=16.8, 3.3 Hz, 1H), 2.5–2.3 (m, 2H),2.19 (dd, J=16.8, 13.2 Hz, 1H), 2.0–1.8 (m, 3H), 1.7–1.2 (m, 5H), 0.89(s, 9H), 0.75 (s, 3H, C18-CH₃), 0.04 (s, 3H), 0.03 (s, 3H).

mp. 159–160° C.

(Step 3)

A solution of17β-(t-butyldimethylsiloxy)-3-methoxyestra-1,3,5(10)-trien-6-one (2.12g, 5 mmol) in anhydrous 1,2-dimethoxyethane (30 ml) was cooled to −70°C. under nitrogen atmosphere, and potassium hexamethyl-disilazide insolid form (1.1 g, 5.5 mmol) was added to the resulting solutionfollowed by stirring for 1 hour while keeping the temperature at −70° C.Distilled allyl iodide (1.68 g, 10 mmol) was then added at −70° C. usinga syringe and the reaction mixture was warmed to 0° C. over 1 hour. Anhour later, water was added at 0° C. to the reaction mixture, which wasthen extracted with ether. The organic layer was washed with water andsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and then filtered. After distilling off the solvent, theresidue was purified by silica gel flash chromatography (eluent:hexane/ethyl acetate=20/1→15/1) to give17β-(t-butyldimethylsiloxy)-3-methoxy-7αβ-(2-propenyl)estra-1,3,5(10)-trien-6-one(2.0 g, Yield 88%). (7α/7β ratio: about 1/6)

The above mixture was dissolved in sodium methoxide solution (0.1 M) andheated under reflux for 2 hours to give a mixture having a 7α/7β ratioof about 7/1.

¹H-NMR(300 MHz, CDCl₃, spectrum of 7α-substituted compound): δ 7.53 (d,1H, J=2.8 Hz, C4-CH), 7.32 (d, 1H, J=8.5 Hz, C1-CH), 7.09 (dd, J=8.5,2.8 Hz, 1H, C2-CH), 5.87–5.72 (m, 1H), 5.02–4.9 (m, 2H), 3.84 (s, 3H,C3-OCH₃), 3.68 (m, 1H), 2.77–2.64 (m, 1H), 2.6–2.54 (m, 1H), 2.4–2.3 (m,2H), 2.22–2.06 (m, 2H), 2.0–1.85 (m, 2H), 1.65–1.2 (m, 6H), 0.9 (s, 9H),0.75 (s, 3H, C18-CH₃), 0.05 (s, 3H), 0.03 (s, 3H).

(Step 4)

17β-(t-Butyldimethylsiloxy)-3-methoxy-7αβ-(2-propenyl)estra-1,3,5(10)-trien-6-one(5.78 g, 12.7 mmol) was dissolved in tetrahydrofuran (30 ml). To thissolution, tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 60 ml)was added, and the resulting mixture was heated under reflux for 4 hoursunder nitrogen atmosphere. After cooling, water was added to thereaction mixture, which was then extracted with ether. The organic layerwas washed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and then filtered. The filtrate was concentrated underreduced pressure to give17β-hydroxy-3-methoxy-7αβ-(2-propenyl)estra-1,3,5(10)-trien-6-one as adiastereomer mixture, which was then recrystallized from diisopropylether (70 ml) to give17β-hydroxy-3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-6-one (2.61g, Yield 60%) as a single isomer.

¹H-NMR(270 MHz, CDCl₃): δ 7.53(d, J=3.0 Hz, 1H, C4-CH), 7.32(d, J=8.5Hz, 1H, C1-CH), 7.09(dd, J=8.5, 3.0 Hz, 1H, C2-CH), 5.84–5.74(m, 1H),5.01–4.92(m, 2H, olefin-H), 3.84(s, 3H, C3-OCH₃), 3.84–3.75(m, 1H,C17-CH), 2.80–2.68(m, 1H, C9-CH), 2.63–2.52(m, 1H, C7-CH), 2.51–2.38(m,2H, allyl-CH₂ and C11-CH₂), 2.24–2.05(m, 3H, allyl-CH₂ and C8-CH andC16-CH₂), 2.02–1.91(m, 1H, C11-CH₂), 1.71–1.33(m, 7H), 0.79(s, 3H,C18-CH₃).

mp 122–123° C.

(Step 5)

Triethylsilane (5 ml) and boron trifluoride diethyl etherate (5 ml) wereadded to a solution of17β-hydroxy-3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-6-one (1.0 g,2.9 mmol) in dichloromethane (20 mL) at 0° C. The resulting mixture waswarmed to room temperature and stirred for 18 hours. After the reactionwas completed, 10% aqueous potassium carbonate was added to the reactionmixture, which was then extracted with ethyl acetate. The organic layerwas washed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and then filtered. After concentration under reducedpressure, the resulting residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=2/1) to give3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol (935 mg, Yield98%).

¹H-NMR(270 MHz, CDCl₃): δ 7.20(d, J=8.6 Hz, C1-1H), 6.71(dd, J=8.6, 2.4Hz, C2-1H), 6.60(d, J=2.4 Hz, C4-1H), 5.86–5.72(m, 1H), 5.00–4.90(m, 2H,olefin-H), 3.77(s, 3H, C3-OCH₃), 3.77–3.71(m, 1H, C17-CH), 2.80–2.68(m,1H, C9-CH), 2.63–2.52(m, 1H, C7-CH), 2.51–2.38(m, 2H, allyl-CH₂ andC11-CH₂), 2.24–2.05(m, 3H, allyl-CH₂ and C8-CH and C16-CH₂),2.02–1.91(m, 1H, C11-CH₂), 1.71–1.33(m, 7H), 0.79(s, 3H, C18-CH₃).

(Step 6)

Benzylidenebis(tricyclohexyl-phosphine)-dichlororuthenium (98 mg, 0.11mmol) was added to a solution of3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol (723 mg, 2.21mmol) and ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate (1.59 g,4.43 mmol) in dichloromethane (20 ml), followed by heating under refluxfor 20 hours under argon atmosphere. After cooling, the reaction mixturewas concentrated under reduced pressure and the resulting residue waspurified by silica gel flash chromatography (eluent: hexane/ethylacetate=4/1) to give ethyl11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-penta-fluoropentyl)-9-undecenoate(973 mg, Yield 67%).

¹H-NMR(270 MHz, CDCl₃): δ 7.20(d, J=8.6 Hz, 1H, C1-CH), 6.76–6.69(m, 1H,C2-CH), 6.63–6.58(m, 1H, C4-CH), 5.42–5.27(m, 2H, olefin-H), 4.15(q,J=7.1 Hz, 2H, COO—CH₂), 3.78–3.70(m, 4H, C17-CH and C3-OCH₃),2.90–2.63(m, 2H), 2.41–2.22(m, 3H), 2.20–1.16(m, 34H), 0.78(s, 3H,C18-CH₃).

(Step 7)

Ethyl11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)-9-undecenoate(970 mg, 1.48 mmol) was dissolved in ethyl acetate (30 ml), and 10%palladium carbon (300 mg) was added to the resulting solution followedby stirring for 4 hours at room temperature under hydrogen atmosphere.The reaction mixture was filtered and concentrated to give ethyl11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-penta-fluoropentyl)undecanoate(946 mg, Yield 97%) as an oil.

¹H-NMR(270 MHz, CDCl₃): δ 7.20(d, J=8.6 Hz, 1H, C1-CH), 6.76–6.69(m, 1H,C2-CH), 6.63–6.58(m, 1H, C4-CH), 4.14(q, J=7.1 Hz, 2H, COO—CH₂), 3.77(s,3H, C3-OCH₃), 3.74(t, J=8.4 Hz, 1H, C17-CH), 2.94–2.70(m, 2H),2.40–2.24(m, 3H), 2.20–1.84(m, 4H), 1.80–0.96(m, 34H), 0.78(s, 3H,C18-CH₃).

(Step 8)

Ethyl11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoate(946 mg, 1.43 mmol) was dissolved in dichloromethane (18 ml). To thissolution, a 1M solution of borane tribromide in dichloromethane (4.3 ml,4.3 mmol) was added dropwise at −78° C. The reaction mixture was warmedslowly and stirred for 3 hours at 0° C. Water was added to stop thereaction and the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, and then filtered. After concentrationunder reduced pressure, the resulting residue was purified by silica gelcolumn chromatography (eluent: hexane/ethyl acetate=2/1) to give ethyl11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoro-pentyl)undecanoate(663 mg, Yield 72%).

¹H-NMR(270 MHz, CDCl₃): δ 7.14(d, J=8.4 Hz, 1H, C1-CH), 6.66–6.59 (m,1H, C2-CH), 6.57–6.53(m, 1H, C4-CH), 5.10(brs, 1H, C3-OH), 4.15(q, J=7.1Hz, 2H, COO—CH₂), 3.75(t, J=8.4 Hz, 1H, C17-CH), 2.94–2.68(m, 2H),2.40–2.22(m, 3H), 2.20–1.84(m, 4H), 1.80–0.96(m, 34H), 0.78(s, 3H,C18-CH₃).

(Step 9)

Ethyl11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoate(660 mg, 1.03 mmol) was dissolved in a mixed solvent of ethanol (10 ml)and water (2.0 ml). To this solution, NaOH (820 mg, 20.5 mmol) wasadded, and the resulting mixture was heated for 4 hours at 60° C. Aftercooling, 2N aqueous hydrochloric acid was added to the reaction mixture,which was then extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and then filtered. After concentration under reducedpressure, the resulting residue was purified by silica gel columnchromatography (eluent: hexane/ethyl acetate=1/1) to give11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid (613 mg, Yield 97%).

¹H-NMR(270 MHz, CD₃OD): δ 7.07(d, J=8.4 Hz, 1H, C1-CH), 6.54 (dd, J=8.4,2.3 Hz, 1H, C2-CH), 6.45(d, J=2.3 Hz, 1H, C4-CH), 3.67(t, J=8.3 Hz, 1H,C17-CH), 2.85–2.62(m, 2H), 2.39–1.84(m, 7H), 1.80–0.96(m, 33H), 0.78(s,3H, C18-CH₃).

Example 14 Synthesis of10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid

Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-olprepared in Example 13 and ethyl2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate prepared separately, thesame procedure as shown in Example 13 was repeated to give10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid.

¹H-NMR(300 MHz, CDCl₃): (7.16(d, J=8.4 Hz, 1H, C1-CH), 6.63(dd, J=8.4Hz, J=2.7 Hz, 1H, C2-CH), 6.55(s, 1H, C4-CH), 3.75(t, J=8.5 Hz, 1H,C17-CH), 3.60–3.35(brs, 1H, C3-OH), 2.82–2.73(m, 2H), 2.45–2.23(m, 4H),2.20–0.96(m, 31H), 0.78(s, 3H, C18-CH₃).

Example 15 Synthesis of10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid

Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-olprepared in Example 13 and ethyl2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared separately,the same procedure as shown in Example 13 was repeated to give10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid.

¹H-NMR (300 MHz; CDCl₃): (7.12(d, J=8.4 Hz, 1H), 6.68(dd, J=8.5, 2.4 Hz,1H), 6.53(d, J=2.6 Hz, 1H), 3.68(t, J=8.5 Hz, 1H), 2.95–2.60(m, 2H),2.47–2.19(m, 4H), 2.18–1.03(m, 31H), 0.69(s, 3H).

Example 16 Synthesis of10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid

Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-olprepared in Example 13 and ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared separately,the same procedure as shown in Example 13 was repeated to give10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid.

¹H-NMR (300 MHz; CDCl₃): (7.14(d, J=8.5 Hz, 1H), 6.62(dd, J=8.2, 2.1 Hz,1H), 6.54(d, J=2.6 Hz, 1H), 3.77(t, J=8.1 Hz, 1H), 2.84–2.56(m, 2H),2.44(m, 1H), 2.31(m, 2H), 2.18–1.02(m, 30H), 0.74(s, 3H).

Example 17 Synthesis of10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid

Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-olprepared in Example 13 and ethyl2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate prepared separately, thesame procedure as shown in Example 13 was repeated to give10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid.

¹H-NMR (300 MHz; CDCl₃): (7.05(d, J=8.4 Hz, 1H), 6.65(dd, J=8.6, 2.6 Hz,1H), 6.52(d, J=2.5 Hz, 1H), 3.75(t, J=8.4 Hz, 1H), 2.92–2.62(m, 2H),2.33–2.12(m, 4H), 2.09–1.03(m, 35H), 0.75(s, 3H).

Example 18 Synthesis of11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoicacid

Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-olprepared in Example 13 and ethyl2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-9-decenoate prepared separately,the same procedure as shown in Example 13 was repeated to give11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoicacid.

¹H-NMR(270 MHz, CDCl₃) δ 7.13(d, J=8.4 Hz, 1H, C1-CH), 6.62 (dd, J=8.4,2.3 Hz, 1H, C2-CH), 6.53(d, J=2.3 Hz, 1H, C4-CH), 3.75(t, J=8.1 and 8.4Hz, 1H, C17-CH), 2.85 (dd, J-4.8 and 16.7 Hz, 1H), 2.70(m, 1H),2.39–1.88(m, 7H), 1.80–0.96(m, 33H), 0.78(s, 3H, C18-CH₃)

Example 19 Synthesis of11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid

Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-olprepared in Example 13 and ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared separately,the same procedure as shown in Example 13 was repeated to give11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid.

¹H-NMR(270 MHz, CD₃OD): δ 7.07(d, J=8.4 Hz, 1H, C1-CH), 6.53 (dd, J8.4,2.2 Hz, 1H, C2-CH), 6.45(d, J=2.2 Hz, 1H, C4-CH), 3.67(t, J=8.1 Hz, 1H,C17-CH), 2.87–2.62(m, 2H), 2.43–0.95(m, 35H), 0.78(s, 3H, C18-CH₃).

Example 20 Synthesis of11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid

(Step 1)

Dimethylformamide (11 ml) was added to β-estradiol (1.08 g, 4.0 mmol)under nitrogen atmosphere, followed by cooling on ice. Sodium hydride(480 mg of 60% suspension) was added to the reaction mixture followed bystirring for 10 minutes on ice and then stirred for 1 hour at roomtemperature. After cooling again on ice, Benzyl bromide (2.05 g, 12mmol) was added to the reaction mixture followed by stirring for 10minutes on ice and then stirred for 20 hours at room temperature. Thereaction mixture was quenched with ice-cold water and extracted withethyl acetate. The organic layer was washed with water and saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate, andthen filtered. The filtrate was concentrated under reduced pressureusing an evaporator and the resulting residue was triturated withmethanol to precipitate solids. The solids were collected by filtrationand vacuum dried to give 3,17β-bis(benzyloxy)estra-1,3,5(10)-triene(1.72 g, Yield 95%).

¹H-NMR(300 MHz, CDCl₃): δ 7.45–7.20(m, 11H), 6.79(dd, J=9.0 and 3.0 Hz,1H, C3-CH), 6.72(d, J=2.7 Hz, 1H, C4-CH), 5.04(s, 2H), 4.56(s, 2H),3.51(t, J=8.1, 1H), 2.88–2.83(m, 2H), 2.36–1.15(m, 13H), 0.88(s, 3H,C18-CH₃).

(Step 2)

Dichloromethane (0.2 ml) and methanol (0.1 ml) were added to3,17β-bis(benzyloxy)estra-1,3,5(10)-triene (45.2 mg, 0.1 mmol) undernitrogen atmosphere, followed by cooling to −78° C.2,3-dichloro-5,6-dicyanobenzoquinone (22.7 mg, 0.1 mmol) was added tothe reaction mixture followed by stirring for 10 minutes at −78° C. andthen stirred for 3 hours at room temperature. The reaction mixture wasquenched with saturated aqueous sodium bicarbonate and extracted withethyl acetate. The organic layer was washed with water and saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate, andthen filtered. The filtrate was concentrated under reduced pressureusing an evaporator and the resulting residue was purified by silica gelcolumn chromatography (Merck Kieselgel 60, eluent: hexane/ethylacetate=10/1→8/1) to give the desired compound3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraene (35.7 mg, Yield 80%).

¹H-NMR(300 MHz, CDCl₃): δ 7.54(d, J=9.0 Hz, 1H, C1-CH), 7.27–7.45(m,10H), 6.80(dd, J=8.7 and 2.7 Hz, 1H, C3-CH), 6.69(d, J=2.4 Hz, 1H,C4-CH), 6.12(m, 1H), 5.05(s, 2H), 4.56(s, 2H), 4.22(m, 1H), 3.60(t,J=8.7 Hz, 1H), 2.97–2.70(m, 2H), 2.43–1.09(m, 9H), 0.87(s, 3H, C18-CH₃).

(Step 3)

Catecholborane (1.0 M in tetrahydrofuran, 66.33 ml) was added to3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraene (27.17 g, 60.30 mmol)at room temperature under nitrogen atmosphere. Lithium borohydride (1.31g, 60.30 mmol) was further added to the reaction mixture at roomtemperature, followed by stirring for 10 hours. Under ice-cooling, thismixture was added to a mixture of sodium hydroxide (24.12 g, 603.0mmol), water (70 ml), ethanol (150 ml) and 30% hydrogen peroxide (150ml), followed by stirring for 1 hour and 45 minutes on ice and thenstirred for 3 hours at room temperature. Ether and water were added tothe reaction mixture, which was then extracted with ether. The organiclayer was washed sequentially with 10% aqueous sodium hydroxide, waterand saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and then filtered. The filtrate was concentrated under reducedpressure using an evaporator. The residue was purified by silica gelcolumn chromatography (Merck Kieselgel 60, eluent: hexane/ethylacetate=6/1→5.5/1) to give the desired compound3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11α-ol (21.56 g, Yield 76%).

¹H-NMR(300 MHz, CDCl₃): δ 7.87(d, J=8.4 Hz, 1H, C1-CH), 7.27–7.45(m,10H), 6.81(dd, J=8.7 and 2.7 Hz, 1H, C3-CH), 6.74(d, J=2.7 Hz, 1H,C4-CH), 5.05(s, 2H), 4.58(s, 2H), 4.22(m, 1H), 3.53(t, J=8.1, 1H),2.82(m, 2H), 2.43(dd, J=12.2 and 5.4 Hz, 1H), 2.18–2.02(m, 2H),1.91–1.84(m, 1H), 1.74–1.59(m, 2H), 1.49–1.27(m, 5H), 0.86(s, 3H,C18-CH3).

(Step 4)

Dichloromethane (92.25 ml) was added to oxalyl dichloride (3.54 ml,40.59 mmol) under nitrogen atmosphere and the resulting mixture wascooled to −78° C. To this mixture, a solution of dimethyl sulfoxide(5.76 ml, 81.18 mmol) diluted in dichloromethane (18.45 ml) was addeddropwise. After the mixture was stirred for 2 minutes at −78° C., asolution of 3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11α-ol (17.29 g,36.90 mmol) in dichloromethane (36.90 ml) was added dropwise, followedby stirring for 15 minutes at −78° C. Triethylamine (25.7 ml, 184.5mmol) was added dropwise to the reaction mixture, which was then stirredfor 5 minutes at −78° C. and warmed to room temperature. The reactionmixture was cooled again on ice, quenched by addition of ice and water,and then extracted with dichloromethane. The organic layer was washedwith water and saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and then filtered. The filtrate was concentratedunder reduced pressure using an evaporator to give crude3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11-one (crude 18.76 g, quantfrom crude ¹H-NMR).

¹H-NMR(300 MHz, CDCl₃): δ 7.41–7.20(m, 11H), 6.82(dd, J=8.4 and 2.7 Hz,1H, C3-CH), 6.70(d, J=2.7 Hz, 1H, C4-CH), 5.03(s, 2H), 4.54(s, 2H),3.72(t, J=8.1 Hz, 1H), 3.46(d, J=10.2 Hz, 1H), 2.84–2.66(m, 3H), 2.47(d,J=11.4 Hz, 1H), 2.23–2.13(m, 1H), 1.96–1.48(m, 8H), 0.86(s, 3H,C18-CH₃).

(Step 5)

Tetrahydrofuran (280 ml) was added to the crude3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11-one (35.7 g, 76.5 mmol)under nitrogen atmosphere, and the resulting mixture was cooled to −40°C. Allylmagnesium chloride (2.0 M in tetrahydrofuran, 50.0 ml, 100 mmol)was added dropwise to the mixture, which was then stirred for 10 minutesat −40° C. and for 1 hour at room temperature. The reaction mixture wascooled again on ice and quenched by addition of ice, water and saturatedaqueous ammonium chloride. After the reaction mixture was extracted withethyl acetate, the organic layer was washed with water and saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate, andthen filtered. The filtrate was concentrated under reduced pressureusing an evaporator and hexane was added to the resulting residue toprecipitate solids. The solids were collected by filtration and vacuumdried to give3,17β-bis(benzyloxy)-11α-(2-propenyl)estra-1,3,5(10)-trien-11β-ol (35.81g, Yield 90% from 3,17β-bis(benzyloxy)estra-1,3,5(10)-trien-11α-ol).

¹H-NMR (300 MHz, CDCl₃): d 7.82 (d, J=9.6 Hz, 1H, C1-H), 7.44–7.33 (m,10H), 6.83–6.79 (m, 2H, C2 and C4-H), 6.01–5.87 (m, 1H, olefin-H),5.21–5.13 (m, 2H, olefin-H), 5.06 (s, 2H), 4.57 (s, 2H), 3.46 (t, J=8.7Hz, 1H, C17-H), 2.90 (dd, J=14.0 and 8.4 Hz, 1H, allylic-CH₂), 2.74–2.63(m, 2H), 2.52 (dd, J=14.1 and 7.0 Hz, 1H, allylic-CH₂), 2.25 (d, J=10.8Hz, 1H), 2.13 (d, J=14.1 Hz, 1H), 2.06–1.98 (m, 1H), 1.88–1.14 (m, 9H),1.09(s, 3H, C18-H).

(Step 6)

After a solution of3,17β-bis(benzyloxy)-11α-(2-propenyl)estra-1,3,5(10)-trien-11β-ol (17.20g, 33.80 mmol) in pyridine (135 ml) was cooled to −40° C. under nitrogenatmosphere, thionyl chloride (3.7 ml, 50.7 mmol) was added dropwise tothe solution, which was then stirred for 10 minutes at −40° C. and for 1hour on ice. The reaction mixture was quenched by addition of ice andwater and then extracted with a mixed solvent of hexane and t-butylmethyl ether (hexane/t-butyl methyl ether=4/1). The organic layer waswashed with water and saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, and then filtered. The filtrate wasconcentrated under reduced pressure using an evaporator and theresulting residue was triturated with methanol to precipitate solids.The solids were collected by filtration and vacuum dried to give3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene(14.92 g, Yield 90%).

¹H-NMR (300 MHz, CDCl₃): d 7.46–7.25 (m, 11H), 6.78–6.75 (m, 2H, C2 andC4-H), 6.01–5.89 (m, 1H, olefin-H), 5.18–5.09 (m, 2H, olefin-H), 5.06(s, 2H), 4.58 (s, 2H), 3.58 (t, J=8.4 Hz, 1H, C17-H), 3.30 (dd, J=15.8and 5.1 Hz, 1H, allylic-CH₂), 2.81–2.72 (m, 3H), 2.48 (d, J=17.4 Hz, 1H,allylic-CH₂), 2.16–1.36 (m, 9H), 0.90 (s, 3H, C18-H).

(Step 7)

Benzylidenebis(tricyclohexylphosphine)-dichlororuthenium (90 mg, 0.1mmol) was added to a solution of3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene (1.0g, 2.0 mmol) and ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate(1.81 g, 4.1 mmol) in dichloromethane (20 ml), followed by heating underreflux for 5 hours under nitrogen atmosphere. After cooling, thereaction mixture was concentrated under reduced pressure and theresulting residue was purified by silica gel flash chromatography(eluent: hexane/ethyl acetate=4/1) to give ethyl11-[3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoate(863 mg, Yield 48%).

¹H-NMR(270 MHz, CDCl₃): δ 7.46–7.21 (m, 11H), 6.78–6.73(m, 2H),5.50–5.42(m, 2H), 5.05(s, 2H), 4.57(d, J=2.5 Hz, 2H), 4.15(q, J=7.1 Hz,2H, COO—CH₂), 3.60–3.52(m, 1H, C17-CH), 3.20–3.11(m, 1H), 2.82–2.68(m,3H), 2.51–2.22(m, 2H), 2.20–1.16(m, 28H), 0.87(s, 3H, C18-CH₃).

(Step 8)

Ethyl11-[3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoate(500 mg, 0.55 mmol) was dissolved in a mixed solvent of methanol (10 ml)and tetrahydrofuran (1 ml), followed by addition of palladiumhydroxide/carbon (150 mg) at room temperature. After purging withhydrogen, the reaction mixture was stirred for 23 hours at roomtemperature and then filtered. The solvent was concentrated underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=4/1→3/1→2/1) to give ethyl11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoate(287 mg, Yield 71%).

¹H-NMR(270 MHz, CDCl₃): δ 7.00(d, J=8.6 Hz, 1H, C1-CH), 6.62(d, J=8.5Hz, 1H, C2-CH), 6.54(d, J=2.3 Hz, 1H, C4-CH), 5.03(brs, 1H, C3-OH),4.17(q, J=7.1 Hz, 2H, COO—CH₂), 3.70(t, J=7.9 Hz, 1H, C17-CH),2.83–2.60(m, 2H), 2.58–2.30(m, 3H), 2.24–1.74(m, 7H), 1.74–1.11(m, 29H),0.92(s, 3H, C18-CH₃).

(Step 9)

Ethyl11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoate(747 mg, 1.02 mmol) was dissolved in a mixed solvent of ethanol (5 ml)and water (5 ml). To this solution, NaOH (82 mg, 2.04 mmol) was added,and the resulting mixture was heated for 15 hours at 60° C. Aftercooling, 2N aqueous hydrochloric acid was added to the reaction mixture,which was then extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and then filtered. After concentration under reducedpressure, the resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate=4/1→3/1→2/1) to give11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid (600 mg, Yield 84%).

¹H-NMR(270 MHz, CD₃OD): δ 6.95(d, J=8.3 Hz, 1H, C1-CH), 6.55(dd, J=8.3,2.3 Hz, 1H, C2-CH), 6.47(d, J=2.3 Hz, 1H, C4-CH), 3.63(t, J=8.6 Hz, 1H,C17-CH), 2.85–2.58(m, 2H), 2.55–2.34(m, 3H), 2.30–1.93(m, 2H),1.91–1.75(m, 3H), 1.75–1.10(m, 26H), 0.92(s, 3H, C18-CH3).

Example 21 Synthesis of10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid

Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene prepared in Example 20 and ethyl2-(4,4,5,5,5-pentafluoro-pentyl)-8-nonenoate prepared separately, thesame procedure as shown in Example 20 was repeated to give10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)decanoicacid.

¹H-NMR(300 MHz, CDCl₃): (6.99(d, J=8.7 Hz, 1H, C1-CH), 6.62(d, J=8.2 Hz,1H, C2-CH), 6.55(d, J=2.3 Hz, 1H, C4-CH), 4.87–3.82(brs, 1H, C3-OH),3.73(t, J=7.4 Hz, 1H, C17-CH), 2.84–2.65(m, 2H), 2.51(m, 1H), 2.39(m,2H), 2.24–1.12(m, 32H), 0.91(s, 3H, C18-CH₃).

Example 22 Synthesis of10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid

Starting with the3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraeneprepared in Example 20 and ethyl2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared separately,the same procedure as shown in Example 20 was repeated to give10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid.

¹H-NMR(300 MHz, CDCl₃): (7.11(d, J=8.3 Hz, 1H, C1-CH), 6.62(d, J=8.6 Hz,1H, C2-CH), 6.54(d, J=2.7 Hz, 1H, C4-CH), 3.94–3.07(brs, 1H, C3-OH),3.72(t, J=7.4 Hz, 1H, C17-CH), 2.82–2.62(m, 2H), 2.52(m, 1H), 2.40(m,2H), 2.23–1.11(m, 32H), 0.91(s, 3H, C18-CH₃)

Example 23 Synthesis of10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid

Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene prepared in Example 20 and ethyl2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared separately,the same procedure as shown in Example 20 was repeated to give10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoicacid.

¹H-NMR (300 MHz; CDCl₃): (=7.07(d, J=8.5 Hz, 1H), 6.65(dd; J=8.2, 2.1Hz, 1H), 6.47(d, J=2.6 Hz, 1H), 3.82(t, J=8.2 Hz, 1H), 2.91–2.58(m, 2H),2.53–2.23(m, 3H), 2.19–1.89(m, 4H), 1.85–1.02(m, 26H), 0.92(s, 3H).

Example 24 Synthesis of11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid

Starting with the3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraeneprepared in Example 20 and ethyl2-(4,4,5,5,5-pentafluoro-pentyl)-9-decenoate prepared separately, thesame procedure as shown in Example 20 was repeated to give11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)undecanoicacid.

¹H-NMR (270 MHz; CDCl₃): (7.00(d, J=8.4 Hz, 1H), 6.59(dd, J=8.7, 2.7 Hz,1H), 6.54(d, J=2.7 Hz, 1H), 3.73–3.71(m, 1H), 2.88–2.82(m, 2H),2.58–2.33(m, 3H), 2.24–1.18(m, 34H), 0.92(s, 3H).

Example 25 Synthesis of11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoicacid

Starting with the3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraeneprepared in Example 20 and ethyl2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-9-decenoate prepared separately,the same procedure as shown in Example 20 was repeated to give11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)undecanoicacid.

¹H-NMR(270 MHz, CD₃OD): δ 7.07(d, J=8.4 Hz, 1H, C1-CH), 6.54 (dd, J=8.4,2.3 Hz, 1H, C2-CH), 6.45(d, J=2.3 Hz, 1H, C4-CH), 3.67(t, J=8.3 Hz, 1H,C17-CH), 2.85–2.62(m, 2H), 2.05–1.80(m, 7H), 1.80–0.96(m, 32H), 0.91(s,3H, C18-CH₃)

Example 26 Synthesis of10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid

The10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(6,6,7,7,7-pentafluoroheptyl)decanoicacid prepared in Example 12 could also be synthesized by a procedureanalogous to Example 20, starting with3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene andseparately prepared ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate.

Example 27 Synthesis of12-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid

Starting with 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthaleneand separately prepared diethyl2-(8-nonenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate, the sameprocedures as shown in Examples 1, 2 and 3 were repeated to give12-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid.

¹H-NMR(270 MHz, CDCl₃): δ 7.98 (d, J=9 Hz, 1H, Ar—H), 7.53 (d, J=8 Hz,1H, Ar—H), 7.28–7.12 (m, 5H, Ar—H), 6.89 (d, J=9 Hz, 2H, Ar—H),2.96–2.90 (m, 2H, naphtyl-CH₂—), 2.44–2.42 (m, 1H, —CHCO₂), 2.18–1.18(m, 24H, alkyl-H).

Example 28 Synthesis of11-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid

Starting with 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthaleneand separately prepared diethyl2-(7-octenyl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate, the sameprocedures as shown in Examples 1, 2 and 3 were repeated to give11-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid.

¹H-NMR(300 MHz, CDCl₃): δ 7.98(d, J=8.9 Hz, 1H, Ar—H), 7.53(d, J=8.4 Hz,1H, Ar—H), 7.13–7.28(m, 5H, Ar—H), 6.89(d, J=8.5 Hz, 2H, Ar—H), 2.92(t,J=8.1 Hz, 2H, naphthyl-CH₂), 2.46–2.48(m, 1H, CHCO₂H), 1.95–2.20(m, 2H,CH ₂CF₂), 1.18–2.11(m, 18H, alkyl-H)

Mass(ESI): 667(M+1)

Example 29 Synthesis of12-[6-hydroxy-2-(4-hydroxy-2-methylphenyl)-naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid

Starting with the 6-methoxy 1-(2-propenyl)-2-naphthyltrifluoromethanesulfonate prepared in Example 1 and4-methoxy-2-methylphenylboronic acid prepared separately, the sameprocedures as shown in Examples 1, 2 and 3 were repeated to give12-[6-hydroxy-2-(4-hydroxy-2-methylphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid.

¹H-NMR(270 MHz, CDCl₃): δ 7.97 (d, J=8.9 Hz, 1H), 7.53 (d, J=8.4 Hz,1H), 7.19–7.10 (m, 3H), 7.02 (d, J=8.3 Hz, 1H), 6.77 (d, J=2.1 Hz, 1H),6.70 (dd, J=8.3, 2.1 Hz, 1H), 4.8 (br, 3H), 3.0–2.8 (m, 1H), 2.7–2.5 (m,1H), 2.5–2.3 (m, 1H), 2.1–1.9 (m, 2H), 1.99 (s, 3H, CH3), 1.8–1.0 (m,22H).

Example 30 Synthesis of12-[2-(2-ethyl-4-hydroxyphenyl)-6-hydroxynaphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid

Starting with the 6-methoxy 1-(2-propenyl)-2-naphthyltrifluoromethanesulfonate prepared in Example 1 and2-ethyl-4-methoxyphenylboronic acid prepared separately, the sameprocedures as shown in Examples 1, 2 and 3 were repeated to give12-[2-(2-ethyl-4-hydroxyphenyl)-6-hydroxynaphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid.

¹H-NMR(300 MHz, CDCl₃): δ 7.97(d, J=9.1 Hz, 1H, Ar—H), 7.52(d, J=8.4 Hz,1H, Ar—H), 7.06–7.23(m, 3H, Ar—H), 6.85(d, J=8.2 Hz, 1H, Ar—H), 6.79(d,J=2.6 Hz, 1H, Ar—H), 6.61(dd, J=8.2, 2.6 Hz, 1H, Ar—H), 2.81–2.93(m, 1H,naphthyl-CH₂), 2.49–2.75(m, 1H, naphthyl-CH₂), 2.39–2.50(m, 1H, CHCO₂H),2.18–2.29(m, 2H, ArCH ₂CH₃), 1.91–2.12(m, 2H, CH ₂CF₂), 0.95–1.72(m,25H, alkyl-H)

Mass(ESI): 623(M+1)

Example 31 Synthesis of12-[2-(2-fluoro-4-hydroxyphenyl)-6-hydroxynaphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid

Starting with the 6-methoxy 1-(2-propenyl)-2-naphthyltrifluoromethanesulfonate prepared in Example 1 and2-fluoro-4-methoxyphenylboronic acid prepared separately, the sameprocedures as shown in Examples 1, 2 and 3 were repeated to give12-[2-(2-fluoro-4-hydroxyphenyl)-6-hydroxynaphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid.

¹H-NMR(300 MHz, CDCl₃): δ 7.97(d, J=9.1 Hz, 1H, Ar—H), 7.52(d, J=8.5 Hz,1H, Ar—H), 7.06–7.25(m, 4H, Ar—H), 6.64–6.69(m, 2H, Ar—H), 2.81–2.90(m,2H, naphthyl-CH₂), 2.40–2.50(m, 1H, CHCO₂H), 1.90–2.10(m, 2H, CH ₂CF₂),1.05–1.75(m, 22H, alkyl-H)

Mass(ESI): 613 (M+1)

Example 32 Synthesis of12-[6-hydroxy-2-(4-hydroxy-2-trifluoromethyl-phenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid

Starting with the 6-methoxy 1-(2-propenyl)-2-naphthyltrifluoromethanesulfonate prepared in Example 1 and4-methoxy-2-trifluoromethylphenylboronic acid prepared separately, thesame procedures as shown in Examples 1, 2 and 3 were repeated to give12-[6-hydroxy-2-(4-hydroxy-2-trifluoromethylphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid.

¹H-NMR(270 MHz, CDCl₃): δ 7.96 (d, J=9 Hz, 1H, Ar—H), 7.50 (d, J=8 Hz,1H, Ar—H), 7.24–7.01 (m, 6H, Ar—H), 2.89–2.84 (m, 1H), 2.51–2.42 (m,2H), 2.11–1.15 (m, 24H, alkyl-H).

Example 33 Synthesis of12-[2-(3-fluoro-4-hydroxyphenyl)-6-hydroxynaphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid

Starting with the 6-methoxy 1-(2-propenyl)-2-naphthyltrifluoromethanesulfonate prepared in Example 1 and3-fluoro-4-methoxyphenylboronic acid prepared separately, the sameprocedures as shown in Examples 1, 2 and 3 were repeated to give12-[2-(3-fluoro-4-hydroxyphenyl)-6-hydroxynaphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid.

¹H-NMR(270 MHz, CDCl₃): δ 7.96 (d, J=9 Hz, 1H, Ar—H), 7.51 (d, J=8 Hz,1H, Ar—H), 7.24–6.95 (m, 6H, Ar—H), 2.94–2.88 (m, 2H, naphtyl-CH₂—),2.39 (m, 1H, —CHCO₂), 2.16–1.18 (m, 24H, alkyl-H).

Example 34 Synthesis of12-[2-(3,5-difluoro-4-hydroxyphenyl)-6-hydroxynaphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid

Starting with the 6-methoxy 1-(2-propenyl)-2-naphthyltrifluoromethanesulfonate prepared in Example 1 and3,5-difluoro-4-methoxyphenylboronic acid prepared separately, the sameprocedures as shown in Examples 1, 2 and 3 were repeated to give12-[2-(3,5-difluoro-4-hydroxyphenyl)-6-hydroxynaphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid.

¹H-NMR(300 MHz, CDCl₃): δ 7.98(d, J=9.9 Hz, 1H, Ar—H), 7.53(d, J=8.5 Hz,1H, Ar—H), 7.14–7.26(m, 3H, Ar—H), 6.85–6.90(m, 2H, Ar—H), 2.88–2.94(m,2H, naphthyl-CH₂), 2.39–2.48(m, 1H, CHCO₂H), 2.01–2.12(m, 2H, CH ₂CF₂),1.24–1.88(m, 21H, alkyl-H).

Mass(ESI): 631(M+1)

Example 35 Synthesis of12-[2-(4-fluorophenyl)-6-hydroxynaphth-1-yl]2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid

Starting with the 6-methoxy 1-(2-propenyl)-2-naphthyltrifluoromethanesulfonate prepared in Example 1 and4-fluorophenylboronic acid prepared separately, the same procedures asshown in Examples 1, 2 and 3 were repeated to give12-[2-(4-fluorophenyl)-6-hydroxynaphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoicacid.

¹H-NMR(270 MHz, CDCl₃): δ 7.98 (d, J=9 Hz, 1H, Ar—H), 7.54 (d, J=8 Hz,1H, Ar—H), 7.31–7.07 (m, 7H, Ar—H), 2.93–2.87 (m, 2H, naphtyl-CH₂—),2.46–2.35 (m, 1H, —CHCO₂), 2.15–1.14 (m, 24H, alkyl-H).

Example 36 Synthesis of(2R)-11-(3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid

(Step 1)

Anhydrous tetrahydrofuran (10 ml) was added to(4S,5R)-3,4-dimethyl-1-(5,5,6,6,7,7,8,8,8-nonafluorooctanoyl)-5-phenylimidazolidin-2-one(1.20 g, 2.5 mmol) under nitrogen atmosphere, and the resulting mixturewas cooled to −78° C. Lithium bis(trimethylsilyl)amide (2.75 ml, 1.0 Min tetrahydrofuran, 2.75 mmol) was added to the mixture, which was thenstirred for 1 hour. After addition of 8-bromo-1-octene (714 mg, 3.0mmol) and HMPA (1.25 ml) at −78° C., the reaction mixture was warmedwith stirring up to −50° C. over 2 hours and up to 0° C. over 30minutes, and then stirred for 12 hours at 0° C. The reaction mixture wasquenched with saturated aqueous ammonium chloride at 0° C., and thenextracted with a mixed solvent of ethyl acetate and n-hexane (3:7). Theorganic layer was washed sequentially with saturated aqueous potassiumbisulfate, saturated aqueous sodium chloride, saturated aqueous sodiumbicarbonate and saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and then filtered. The filtrate was concentratedunder reduced pressure using an evaporator and the resulting residue waspurified by silica gel column chromatography (Kanto Kagaku, silica gel60 (spherical, neutral), 40–100 μm, eluent: ethyl acetate/n-hexane=1/53/7) to give(4S,5R)-3,4-dimethyl-1-[(2R)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoyl]-5-phenylimidazolidin-2-one(1.37 g, Yield 93%).

Optical purity: 95.5% de, as measured by HPLC (column: Daicel ChiralpackAD, φ0.46×25 cm, solvent: n-hexane/isopropanol=97/3, flow rate: 0.5ml/min, detection wavelength: 206 nm)

¹H-NMR(270 MHz, CDCl₃): δ 7.32–7.13 (m, 5H), 5.87–5.72 (m, 1H), 5.34(d,J=8.9 Hz, 1H), 5.02–4.91 (m, 2H), 4.10–3.86 (m, 2H), 2.84 (s, 3H),2.19–1.08 (m, 16H), 0.82 (d, J=6.5 Hz, 3H).

(Step 2)

3-Methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol (377 mg, 1.16mmol) and(4S,5R)-3,4-dimethyl-1-[(2R)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoyl]-5-phenylimidazolidin-2-one(1.36 g, 2.31 mmol) were dissolved in anhydrous dichloromethane (12 ml)at room temperature under nitrogen atmosphere. To this solution,benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (47.5 mg,5.78×10⁻² mmol) was added, and the resulting mixture was heated underreflux for 5 hours under nitrogen atmosphere. After cooling, thereaction mixture was filtered through an alumina pad. The filtrate wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel flash chromatography (Kanto Kagaku, silica gel 60(spherical, neutral), 40–100 μm, eluent: ethyl acetate/n-hexane=1/1) togive a mixture of(4S,5R)-3,4-dimethyl-1-[(2R,9E)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl]-5-phenylimidazolidin-2-oneand(4S,5R)-3,4-dimethyl-1-[(2R,9Z)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl]-5-phenylimidazolidin-2-one(579 mg, Yield 57%).

¹H-NMR(300 MHz, CDCl₃): δ 7.33–7.12 (m, 6H), 6.73–6.69 (m, 1H),6.61–6.56 (m, 1H), 5.42–5.25 (m, 3H), 4.05–3.87 (m, 2H), 3.77–3.70 (m,4H), 2.90–2.71 (m, 5H), 2.38–1.06 (m, 31H), 0.83–0.78 (m, 6H).

(Step 3)

The mixture of(4S,5R)-3,4-dimethyl-1-[(2R,9E)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl]-5-phenylimidazolidin-2-oneand(4S,5R)-3,4-dimethyl-1-[(2R,9Z)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl]-5-phenylimidazolidin-2-one(579 mg, 653 μmol) was dissolved in ethyl acetate (14 ml), followed byaddition of 10% palladium carbon (58 mg) at room temperature. Afterpurging with hydrogen, the reaction mixture was stirred for 19 hours atroom temperature. After the reaction mixture was filtered throughcellite, the solvent was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (Kanto Kagaku,silica gel 60 (spherical, neutral), 40–100 μm, eluent: ethylacetate/n-hexane=1/1) to give(4S,5R)-3,4-dimethyl-1-[(2R)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoyl]-5-phenylimidazolidin-2-one(579 mg, Yield 100%).

¹H-NMR(300 MHz, CDCl₃): δ 7.33–7.11 (m, 6H), 6.73–6.70 (m, 1H),6.69–6.62 (m, 1H), 5.33 (d, J=7.8 Hz, 1H), 4.05–3.86 (m, 2H), 3.79–3.71(m, 1H), 3.77 (s, 3H), 2.94–2.72 (m, 2H), 2.84 (s, 3H), 2.38–0.99 (m,35H), 0.82 (d, J=5.9 Hz, 3H), 0.78 (s, 3H).

(Step 4)

(4S,5R)-3,4-Dimethyl-1-[(2R)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoyl]-5-phenylimidazolidin-2-one(445 mg, 0.50 mmol) was dissolved in anhydrous ethylene glycol dimethylether (5 ml) under nitrogen atmosphere and then cooled to 0° C. To thissolution, tetra-n-butylammonium hydroxide solution (40% w/w, 649 mg, 1.0mmol) and aqueous hydrogen peroxide (30% w/w, 113 mg, 1.0 mmol) wereadded, and the resulting mixture was stirred for 1.5 hours at roomtemperature. The reaction mixture was quenched with saturated aqueoussodium thiosulfate, acidified with saturated aqueous potassiumbisulfate, and then extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and then filtered. The filtrate was concentratedunder reduced pressure using an evaporator and the resulting residue waspurified by silica gel column chromatography (Wako gel C-200, eluent:ethyl acetate/n-hexane=4/6→8/2) to give(2R)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid (360 mg, Yield 100%) and(4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one (93 mg, Yield 98%).

¹H-NMR(300 MHz, CDCl₃): δ 7.21–7.18 (m, 1H), 6.73–6.69 (m, 1H),6.62–6.61 (m, 1H), 6.30 (bs, 1H), 3.79–3.71 (m, 1H), 3.77(s, 3H),2.93–2.72 (m, 2H), 2.47–1.01 (m, 36H), 0.78 (s, 3H).

(Step 5)

Anhydrous dichloromethane (10 ml) was added to(2R)-11-(17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid (358 mg, 0.50 mmol) under nitrogen atmosphere and the resultingmixture was cooled to −78° C. Boron tribromide (1.0 M intetrahydrofuran, 3.0 ml, 3.0 mmol) was added dropwise to the mixture,which was then stirred on ice for 2.5 hours. The reaction mixture wascooled again to −78° C. and quenched with saturated aqueous sodiumbicarbonate over 1 hour. After the reaction mixture was extracted withethyl acetate, the organic layer was washed sequentially with saturatedaqueous potassium bisulfate, saturated aqueous sodium chloride,saturated aqueous sodium bicarbonate and saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, and then filtered. Thefiltrate was concentrated under reduced pressure using an evaporator andthe resulting residue was purified by silica gel column chromatography(Wako gel C-200, eluent: ethyl acetate/n-hexane=4/6) to give(2R)-11-(3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoicacid (231 mg, Yield 60%) as a yellow amorphous mass.

Chemical purity: 99.05% and 98.63% at detection wavelengths of 280 and219 nm, respectively, as measured by HPLC (column: YMC-Pack ODS-A, A-312φ0.6×15 cm, solvent: H₂O/MeCN/TFA=30/70/0.1, flow rate: 1.0 ml/min)

Optical purity: 96.3% de, as measured by HPLC (column: Daicel ChiralpackAD, φ0.46×25 cm, solvent: n-hexane/isopropanol/TFA=90/10/0.1, flow rate:0.5 ml/min, detection wavelength: 280 nm)

¹H-NMR(270 MHz, CDCl₃): δ 7.16–7.13 (m, 1H), 6.64–6.60 (m, 1H),6.55–6.54_(m, 1H), 3.74 (t, J=8.6 Hz, 1H), 2.91–2.67 (m, 2H), 2.50–1.01(m, 36H), 0.78 (s, 3H).

Example 37 Synthesis of(2R)-10-(3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid

Starting with 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol andthe(4S,5R)-3,4-dimethyl-1-[(2R)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoyl]-5-phenylimidazolidin-2-oneprepared separately by a procedure analogous to Example 36, analogousprocedure to Example 36 was repeated to give(2R)-10-(3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid.

¹H-NMR (300 MHz; CDCl₃): δ 7.12(d, J=8.4 Hz, 1H), 6.68(dd, J=8.5, 2.4Hz, 1H), 6.53(d, J=2.6 Hz, 1H), 3.68(t, J=8.5 Hz, 1H), 2.95–2.60(m, 2H),2.47–2.19(m, 4H), 2.18–1.03(m, 31H), 0.69(s, 3H).

Example 38 Synthesis of(2S)-10-(3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid

Stating with 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol andthe(4R,5S)-3,4-dimethyl-1-[(2S)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoyl]-5-phenylimidazolidin-2-oneprepared separately by a procedure analogous to Example 36, analogousprocedure to Example 36 was repeated to give(2S)-10-(3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoicacid.

¹H-NMR (300 MHz; CDCl₃): δ 7.12(d, J=8.4 Hz, 1H), 6.68(dd, J=8.5, 2.4Hz, 1H), 6.53(d, J=2.6 Hz, 1H), 3.68(t, J=8.5 Hz, 1H), 2.95–2.60(m, 2H),2.47–2.19(m, 4H), 2.18–1.03(m, 31H), 0.69(s, 3H).

Example 39 Synthesis of(2R)-11-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanicacid

(Step 1)

3,17β-Bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene (491mg, 1.00 mmol) and the(4S,5R)-3,4-dimethyl-1-[(2R)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoyl]-5-phenylimidazolidin-2-one(1.18 g, 2.00 mmol) prepared in Example 36 were dissolved in anhydrousdichloromethane (10 ml) at room temperature under nitrogen atmosphere,mixed with benzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (41mg, 0.05 mmol), and then heated under reflux followed by stirring for 6hours under nitrogen atmosphere. After cooling, the reaction mixture wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel flash chromatography (eluent: ethylacetate/n-hexane=3/7) to give a mixture of(4S,5R)-1-{(2R,9E)-11-[3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-oneand(4S,5R)-1-{(2R,9Z)-11-[3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one(664 mg, Yield 63%).

¹H-NMR(270 MHz, CDCl₃): δ 7.45–7.10(m, 16H), 6.78–6.70(m, 2H),5.58–5.40(m, 2H), 5.32(d, J=8.7 Hz, 1H), 5.04(s, 2H), 4.65–4.50(m, 2H),4.10–3.80(m, 2H), 3.62–3.50(m, 1H), 3.22–3.05(m, 1H), 2.83(s, 3H),2.80–2.60(m, 3H), 2.52–2.30(m, 1H), 2.20–1.0(m, 25H), 0.87(s, 3H,C18-CH₃), 0.81(d, J=6.6 Hz, 3H).

(Step 2)

The mixture of(4S,5R)-1-{(2R,9E)-11-[3,17β-bis-(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-oneand(4S,5R)-1-{(2R,9Z)-11-[3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one(283 mg, 0.27 mmol) was dissolved in a mixed solvent of methanol (12 ml)and tetrahydrofuran (1.2 ml), followed by addition of palladiumhydroxide/carbon (85 mg) at room temperature. After purging withhydrogen, the reaction mixture was stirred for 1 day at roomtemperature. After the reaction mixture was filtered, the solvent wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: ethyl acetate/n-hexane=3/7) to give(4S,5R)-1-{(2R)-11-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one(164 mg, Yield 70%).

¹H-NMR(300 MHz, CDCl₃): δ 7.36–7.12(m, 5H), 6.94–6.88(m, 1H), 6.56–6.52(m, 1H), 6.44–6.36(m, 1H), 5.64(s, 1H), 5.35(d, J=8.7 Hz, 1H),5.70–5.15(m, 3H), 4.38(s, 3H), 4.40–2.60(m, 36H), 2.43(s, 3H), 2.34(d,J=6.6 Hz, 3H).

(Step 3)

(4S,5R)-1-{(2R)-11-[3,17β-Dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one(140 mg, 0.16 mmol) was dissolved in DME (3 ml). To this solution,tetra-n-butylammonium hydroxide solution (40% w/w, 312 mg, 0.48 mmol)and aqueous hydrogen peroxide (30% w/w, 56 mg, 0.48 mmol) were added,and the resulting mixture was stirred for 2 hours at room temperature.The reaction mixture was quenched with 10% aqueous sodium sulfite,acidified with 2N hydrochloric acid, and then extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, and then filtered. Thefiltrate was concentrated under reduced pressure and the resultingresidue was purified by silica gel column chromatography (Wako gelC-200, eluent: ethyl acetate/n-hexane=3/7), then by preparative HPLC(YMC-ODS-5-B (3×25 cm), eluent: acetonitrile/water/ trifluoroaceticacid=90/10/0.1, flow rate: 18 mL/min), to give the desired compound(2R)-11-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanicacid (58 mg, Yield 52%).

¹H-NMR(300 MHz, CDCl₃): δ 7.00(d, J=8.4 Hz, 1H, C1-CH), 6.55(dd, J=8.4,2.4 Hz, 1H, C2-CH), 6.54(d, J=2.4 Hz, 1H, C4-CH), 3.75(t, J=7.5 Hz, 1H),2.85–1.10(m, 38H), 0.92(s, 3H, C18-CH3).

Chemical purity: 98.4%, as measured by HPLC (column: YMC-Pack ODS-A,A-312 φ0.6×15 cm, solvent: H₂O/MeCN/TFA=30/70/0.1, flow rate: 1.0ml/min, detection wavelength: 220 nm)

Optical purity: 95.7%de, as measured by HPLC (column: Daicel ChiralpackAD, φ0.46×25 cm, solvent: n-hexane/i-propanol/TFA=92/8/0.08, flow rate:0.5 ml/min, detection wavelength: 280 nm)

Test Example 1 Anti-estrogenic Activity (Oral Administration)

Test compounds were assayed for their oral anti-estrogenic activity inthe following manner. In this experiment, the compounds prepared inExamples 5, 12, 14–33, 37 and 38 were used as test compounds. As controlcompounds, those having the same structures in the parent scaffold asthe test compounds were used, that is, ZM189154 for Examples 5 and 27–33and ICI182780 for Examples 12, 14–26, 37 and 38.

To determine anti-estrogenic activity, mice (ICR, weight 30±2 g) whichhad been ovariectomized 2 weeks before were subcutaneously administeredwith 17β-estradiol-benzoate (Sigma) in an amount of 0.1 μg/mouse for 3days and the degree by which the test compound inhibited the increase inuterine weight was measured. In this experiment, each of the test andcontrol compounds was suspended in 5% arabic gum solution and orallyadministered for 3 days on a once-a-day basis. After 24 hours from thelast administration, the test animals were sacrificed and the uteri wereremoved and weighed. The results obtained are shown in Table 2 below.

TABLE 2 Anti-estrogenic activity in ovariectomized mice administeredwith 17β-estradiol (oral administration, 3 days) Test compound/dose(p.o., 3 days) Compound mg/kg Inhibition (%) Example 5  10 67 Example 2710 64 Example 28 10 68 Example 29 10 80 Example 30 10 58 Example 31 1075 Example 32 10 73 Example 33 10 64 ZM189154 10 42 Example 12 10 97Example 14 10 87 Example 15 10 96 Example 16 10 98 Example 17 10 94Example 18 10 85 Example 19 10 92 Example 20 10 94 Example 21 10 99Example 22 10 98 Example 23 10 98 Example 24 10 98 Example 25 10 93Example 26 10 96 Example 37 10 101 Example 38 10 100 ICI182780 10 51

The results shown in Table 2 above indicate that the compounds having aside chain of general formula (1) according to the present inventionshow a superior inhibitory activity against the estradiol-inducedincrease in uterine weight, as compared to the anti-estrogenic controlcompounds ZM189154 and ICI182780 which have the same parent scaffold butno such side chain.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have a side chain of generalformula (1). This side chain allows the compounds of the presentinvention to show an improved bioavailability and a significantlyincreased activity following oral administration, as compared to theconventional compounds lacking that side chain, such as compounds havinglow activity following oral administration, compounds having anti-tumoractivity, compounds having estrogenic activity or compounds havinganti-estrogenic activity. The compounds of the present invention aretherefore advantageous in pharmaceutical use.

1. A compound having the following formula (2):

in which R₁ represents a hydrogen atom or a salt-forming metal, R₂represents a linear or branched C₁–C₇ halogenoalkyl group, m representsan integer of 2 to 14, n represents an integer of 2 to 7, and Arepresents a group selected from the following formulae (5) to (8), (10)to (16) and (21) to (24):

in which in formulae (6), (7), and (14), each of R₃ and R₆ represents alinear or branched C₁–C₅ alkyl group, in formulae (10), (11) and (12),Z₁₀ represents a hydrogen atom or an acyl group, in formulae (13), (21)and (22), each of Z₁, Z₂, Z₃, Z₄, Z₅ and Z₆ independently represents ahydrogen atom, a hydroxyl group or a linear or branched C₁–C₅ alkylgroup, in formula (15), R₇ represents a hydrogen atom or a linear orbranched C₁–C₅ alkyl group, in formula (16), each of Z₇, Z₈ and Z₉independently represents a hydrogen atom or a hydroxyl group, in formula(23), each of R₂₁, R₂₂, R₂₃ and R₂₄ independently represents a hydrogenatom, a linear or branched C₁–C₅ alkyl group, a linear or branched C₁–C₇halogenoalkyl group, a halogen atom or an acyl group, or an enantiomerof the compound, or a pharmaceutically acceptable salt of the compoundor enantiomer thereof.
 2. The compound or an enantiomer thereof, or apharmaceutically acceptable salt of the compound or an enantiomerthereof according to claim 1, wherein R₂ is a linear or branched C₁–C₅perhalogenoalkyl group or a group of the following general formula (9):

in which each of R₄ and R₅ which may be the same or different representsa linear or branched C₁–C₃ perhalogenoalkyl group.
 3. The compound or anenantiomer thereof, or a pharmaceutically acceptable salt of thecompound or an enantiomer thereof according to claim 2, wherein ahalogen atom in the halogenoalkyl group is a fluorine atom.
 4. Ananti-estrogenic pharmaceutical composition comprising the compoundaccording to claim 1 as an active ingredient.
 5. The compound or anenantiomer thereof, or a pharmaceutically acceptable salt of thecompound or an enantiomer thereof according to claim 1, wherein ahalogen atom in the halogenoalkyl group is a fluorine atom.
 6. Thecompound or an enantiomer thereof, or a pharmaceutically acceptable saltof the compound or an enantiomer thereof according to claim 2 wherein Ais a group of formula (5), (6), (7), (8), (10), (11), (12), (13), (14),(15), (16), (21), (22) or (23), and m is an integer of 4 to
 10. 7. Thecompound or an enantiomer thereof, or a pharmaceutically acceptable saltof the compound or an enantiomer thereof according to claim 1, wherein acarbon atom in formula (2), to which —COOR is attached, takes R- orS-configuration.
 8. The compound or an enantiomer thereof, or apharmaceutically acceptable salt of the compound or enantiomer thereofaccording to claim 2, wherein a carbon atom in formula (2), to which—COOR is attached, takes R- or S-configuration.
 9. A pharmaceuticalcomposition comprising the compound according to claim 1 as an activeingredient.
 10. A pharmaceutical composition comprising the compoundaccording to claim 2 as an active ingredient.
 11. A pharmaceuticalcomposition comprising the compound according to claim 3 as an activeingredient.
 12. A method for treating breast cancer comprisingadministering to a patient in need thereof a compound according toclaim
 1. 13. A method for treating breast cancer comprisingadministering to a patient in need thereof a compound according to claim2.
 14. A method for treating breast cancer comprising administering to apatient in need thereof a compound according to claim 3.